molecules

Review Amidoximes and Oximes: Synthesis, Synthesis, Structure, and Theirand Their Key KeyRole Role as NO as Donors NO Donors

Tanya Sahyoun 11, Axelle Arrault 1,** and and Raphaël Raphaël Schneider Schneider 2,2,** 11 LaboratoireLaboratoire de de Chimie Chimie Physique Physique Macromoléculaire Macromoléculaire,, Université Universit édede Lorraine, Lorraine, CNRS, CNRS, LCPM, LCPM, F-54000 Nancy, FranceF-54000 Nancy, France 22 LaboratoireLaboratoire Réactions Réactions et et Génie Génie des des Procédés, Procédés, Univer Universitsité édede Lorraine, Lorraine, CNRS, CNRS, LRGP, LRGP, F-54000 F-54000 Nancy, Nancy, France France * Correspondence:Correspondence: axelle.arrault@univ [email protected] (A.A.); (A.A.); raphael.schneid [email protected]@univ-lorraine.fr (R.S.); (R.S.); Tel.: +33- 372743689Tel.: +33-372743689 (A.A.); +33-372743790 (A.A.); +33-372743790 (R.S.) (R.S.) Received: 20 June 2019; Accepted: 2 July 2019; Published: 5 July 2019


Received: 20 June 2019; Accepted: 2 July 2019; Published: 5 July 2019
 Abstract: Nitric oxide (NO) is naturally synthesized in the human body and presents many Abstract: Nitric oxide (NO) is naturally synthesized in the human body and presents many beneficial beneficial biological effects; in particular on the cardiovascular system. Recently; many researchers biological effects; in particular on the cardiovascular system. Recently; many researchers tried to tried to develop external sources to increase the NO level in the body; for example by using develop external sources to increase the NO level in the body; for example by using amidoximes amidoximes and oximes which can be oxidized in vivo and release NO. In this review; the classical and oximes which can be oxidized in vivo and release NO. In this review; the classical methods methods and most recent advances for the synthesis of both amidoximes and oximes are presented and most recent advances for the synthesis of both amidoximes and oximes are presented first. first. The isomers of amidoximes and oximes and their stabilities will also be described; (Z)- The isomers of amidoximes and oximes and their stabilities will also be described; (Z)-amidoximes amidoximes and (Z)-oximes being usually the most energetically favorable isomers. This and (Z)-oximes being usually the most energetically favorable isomers. This manuscript details also manuscript details also the biomimetic and biological pathways involved in the oxidation of the biomimetic and biological pathways involved in the oxidation of amidoximes and oximes. The key amidoximes and oximes. The key role played by cytochrome P450 or other dihydronicotinamide- role played by cytochrome P450 or other dihydronicotinamide-adenine dinucleotide phosphate adenine dinucleotide phosphate (NADPH)-dependent reductase pathways is demonstrated. (NADPH)-dependent reductase pathways is demonstrated. Finally, amidoximes and oximes exhibit Finally, amidoximes and oximes exhibit important effects on the relaxation of both aortic and important effects on the relaxation of both aortic and tracheal rings alongside with other effects as the tracheal rings alongside with other effects as the decrease of the arterial pressure and of the thrombi decrease of the arterial pressure and of the thrombi formation formation Keywords: amidoxime; oxime; synthesis; isomerism; nitric oxide; oxidation Keywords: Amidoxime; oxime; synthesis; isomerism; nitric oxide; oxidation

1. Introduction 1. Introduction In recent years, oximes and amidoximes (oximes in which one of the substituents is an amino In recent years, oximes and amidoximes (oximes in which one of the substituents is an amino group) (Figure1) have gained high interest. These compounds are usually easy to synthesize and group) (Figure 1) have gained high interest. These compounds are usually easy to synthesize and were studied in many different fields such as coordination [1] or materials chemistry [2,3] but also for were studied in many different fields such as coordination [1] or materials chemistry [2,3] but also their numerous biological activities. Moreover, the amidoxime function is often used as bioisoster of a for their numerous biological activities. Moreover, the amidoxime function is often used as bioisoster carboxylic acid, and there are some successful examples of drug candidates exhibiting cardiotonic or of a carboxylic acid, and there are some successful examples of drug candidates exhibiting cardiotonic antiarthritic properties containing the amidoxime moiety. or antiarthritic properties containing the amidoxime moiety.

R NH2 R H R R'

N N N OH OH OH

Amidoxime Aldoxime Ketoxime

Oxime Figure 1. Structures of amidoximes and oximes. Figure 1. Structures of amidoximes and oximes. Oximes and amidoximes have also gained high interest regarding their ability to release nitric oxideOximes (NO). and The amidoximes oxidation of have these also compounds gained high can inte berest catalyzed regarding by their various ability hemoproteins to release nitric like oxidecytochrome (NO). P450The (CYP450)oxidation orof horseradishthese compounds peroxidase can (HRP)be catalyzed [4]. The by first vari stepous of hemoproteins arginine oxidation like cytochrome P450 (CYP450) or horseradish peroxidase (HRP) [4]. The first step of arginine oxidation

Molecules 2019,, 24,, x; 2470; doi: doi: 10.3390/molecules24132470 www.mdpi.comwww.mdpi.com/journal/molecules/journal/molecules Molecules 2019, 24, 2470 2 of 19

Molecules 20192019,, 2424,, xx 22 ofof 1818 has been extensively studied since the intermediate product, N-hydroxy-l-arginine (NOHA) exhibiting hasan amidoximebeen extensively function, studied is oxidized since by the NO-synthase intermediate (NOS) product, and otherN-hydroxy--hydroxy- enzymesLL-arginine-arginine like CYP450 (NOHA)(NOHA) into exhibitingNOexhibiting (Figure anan2)[ amidoximeamidoxime5]. NO is function,function, involved isis in oxidizedoxidized many physiological byby NO-synthaseNO-synthase processes (NOS)(NOS) such andand as otherother neurotransmission, enzymesenzymes likelike CYP450blood pressure into NO regulation, (Figure or2) immunomodulation. [5]. NO is involveded Thus, inin itmanymany is important physiologicalphysiological to have processesprocesses external sources suchsuch asas of neurotransmission,NO specially when NOSblood presents pressure an regulation, abnormal activity or immunomodulation. as it is the case for Thus, patients it is having important diseases to have like externaldiabetesexternal sourcessources or hypertension ofof NONO speciallyspecially [6,7]. For whenwhen this NOSNOS reason, presentspresents exogenous anan abnormalabnormal compounds activityactivity able asas to itit be isis oxidized thethe casecase for byfor dipatientspatientsfferent havingpathways diseases that do like not diabetes involve or NOS hypertension are of high [6,7 interest.].]. ForFor thisthis reason,reason, exogenousexogenous compoundscompounds ableable toto bebe oxidized by different pathways that do not involve NOS are of high interest.

Figure 2. In vivo NO synthesis from arginine. Figure 2. InIn vivovivo NONO synthesissynthesis fromfrom arginine.arginine. Microsomal oxidation of amidoximes generates the corresponding amides and/or nitriles. It has Microsomal oxidation of amidoximes generates thee correspondingcorresponding amidesamides and/orand/or nitriles.nitriles. ItIt hashas been demonstrated that these oxidative cleavages of C=N bonds to the corresponding C=O bonds result been demonstrated that these oxidative cleavagess ofof C=NC=N bondsbonds toto thethe correspondingcorresponding C=OC=O bondsbonds in a transfer of one oxygen atom (dependent on CYP450) from O2 to the substrate, with simultaneous resultresult inin aa transfertransfer ofof oneone oxygenoxygen atomatom (dependent(dependent onon CYP450)CYP450) fromfrom OO22 toto thethe substrate,substrate, withwith release of NO [8]. simultaneoussimultaneous relerelease of NO [8]. In 1986, a patent was deposited for a series of compounds containing an amidoxime function InIn 1986,1986, aa patentpatent waswas depositeddeposited forfor aa seriesseries ofof compoundscompounds containingcontaining anan amidoximeamidoxime functionfunction possessing cardiotonic activities and allowing an increase in the heart muscle force [9]. In 1989, possessing cardiotonic activities and allowing an increasecrease inin thethe heartheart musclemuscle forceforce [9].[9]. InIn 1989,1989, aa a second patent proved that many compounds bearing amidoxime functions can reduce heart failures secondsecond patentpatent provedproved thatthat manymany compoundscompounds bearinbearing amidoxime functions can reduce heart failures by increasing the contractile force of the heart muscle [10]. These studies were followed by the work by increasing the contractile force of the heart muscle [10]. These studies were followed by the work of Shahid et al. who demonstrated that once the cardiotonic agent depicted in Figure3 injected in of Shahid et al. who demonstrated that once the cardiotonicrdiotonic agentagent depicteddepicted inin FigureFigure 33 injectedinjected inin isolated cardiac and vascular tissues, positive chronotropic and inotropic effects were observed [11]. isolatedisolated cardiaccardiac andand vascularvascular tissues,tissues, positivepositive chrochronotropic and inotropic effects were observed [11]. O O NH2 .HCl.HCl NOH O

FigureFigure 3. StructureStructure ofof NN-hydroxy-5,6-dimethoxy-1-hydroxy-5,6-dimethoxy-1-hydroxy-5,6-dimethoxy-1HH-indene-2-carboximidamide.HCl.-indene-2-carboximidamide.HCl. The oxidations of oximes and amidoximes were studied in vitro using either chemical reagents like The oxidations of oximes and amidoximes were studied in vitro using either chemical reagents 2-iodobenzoic acid (IBX) or IBX associated to tetraethylammonium bromide (TEAB) [12] or biological likelike 2-iodobenzoic2-iodobenzoic acidacid (IBX)(IBX) oror IBXIBX associatedassociated toto tetraethylammoniumtetraethylammonium bromidebromide (TEAB)(TEAB) [12][12] oror ones like microsomes of rats containing CYP450 [5]. Amidoximes are also known to be reduced biological ones like microsomes of rats containing CYP450CYP450 [5].[5]. AmidoximesAmidoximes areare alsoalso knownknown toto bebe in vivo into amidines exhibiting important anti-microbial activities against many pathogens such as reducedreduced inin vivovivo intointo amidinesamidines exhibitingexhibiting importanimportantt anti-microbialanti-microbial activitiesactivities againstagainst manymany pathogenspathogens pneumocystis and protozoan [13,14]. suchsuch asas pneumocystispneumocystis and protozoan [13,14]. In this review, we focus on the oxidation methods of both amidoximes and oximes developed InIn thisthis review,review, wewe focusfocus onon thethe oxidationoxidation methodsmethods ofof bothboth amidoximesamidoximes andand oximesoximes developeddeveloped over the last twenty years, topic that has never been described to date. The first part is devoted to the over the last twenty years, topic that has never been describeddescribed toto date.date. TheThe firstfirst partpart isis devoteddevoted toto thethe structure and isomerism of these compounds, which is an important subject only scarcely presented in structurestructure andand isomerismisomerism ofof thesethese compounds,compounds, whichwhich isis anan importantimportant subjectsubject onlyonly scarcelyscarcely presentedpresented the literature. Next, the major methods developed for the synthesis of amidoximes and oximes will be inin thethe literature.literature. Next,Next, thethe majormajor methodsmethods developedeveloped for the synthesis of amidoximes and oximes will reported. Finally, the last part will describe the in vitro oxidation steps of amidoximes and oximes via be reported. Finally, the last part will describe the in vitro oxidation steps of amidoximes and oximes chemical as well as biological processes. The oxidation mechanisms will also be presented in order to via chemical as well as biological processes. The oxidation mechanisms will also be presented in order describe the exact pathways of NO release. Finally, the last part will focus on the in vivo oxidations of toto describedescribe thethe exactexact pathwayspathways ofof NONO release.release. Finally,Finally, thethe lastlast partpart willwill focusfocus onon thethe inin vivovivo oxidationsoxidations amidoximes and oximes in rats and rabbits alongside with their effects like the release of NO, the blood of amidoximes and oximes in rats and rabbits alongsideide withwith theirtheir effectseffects likelike thethe releaserelease ofof NO,NO, thethe pressure regulation and the vasodilatation. blood pressure regulation andand thethe vasodilatation.vasodilatation. 2. Isomerism of Amidoximes and Oximes 2. Isomerism of Amidoximes and Oximes Amidoximes and oximes have poorly been studied in the literature regarding their isomerism. Amidoximes and oximes have poorly been studied in the literature regarding their isomerism. However, this topic is of high interest for the determination of their structure. These two compounds However, this topic is of high interest for the determinationtermination ofof theirtheir structure.structure. TheseThese twotwo compoundscompounds can exhibit two types of isomers, (i) geometrical diastereoisomers Z or E, and (ii) constitutional isomers cancan exhibitexhibit twotwo typestypes ofof isomers,isomers, (i)(i) geometricalgeometrical diastereoisomersdiastereoisomers Z or E,E, andand (ii)(ii) constitutionalconstitutional isomersisomers (tautomers).(tautomers). BetterBetter knowledgeknowledge ofof thethe relativerelative stabilitystability ofof thethe tautomerictautomeric formsforms ofof amidoximesamidoximes

Molecules 2019, 24, x 3 of 18

Moleculeswould permit2019, 24, to 2470 elucidate some aspects of their pharmacological activity, of their reactivity and3 of 19of their ability to coordinate with metal centers. Some studies were devoted to amidoximes in order to clarify their structure. Four main (tautomers). Better knowledge of the relative stability of the tautomeric forms of amidoximes would amidoxime tautomers plus their geometrical isomers (Z/E) were studied, namely amidoxime, permit to elucidate some aspects of their pharmacological activity, of their reactivity and of their ability iminohydroxylamine, aminonitrone and nitroso-amine (Figure 4) [15,16]. In 1964, the presence of a to coordinate with metal centers. zwitterionic form for amidoximes was demonstrated. This zwitterion or aminonitrone was identified Some studies were devoted to amidoximes in order to clarify their structure. Four main amidoxime via FT-IR by the presence of a medium to strong band at 1690 cm−1 associated to the amidoxime C=N tautomers plus their geometrical isomers (Z/E) were studied, namely amidoxime, iminohydroxylamine, stretching at 1656 cm−1. The main aminonitrone and amidoxime IR bands are summarized in Table 1 aminonitrone and nitroso-amine (Figure4)[ 15,16]. In 1964, the presence of a zwitterionic form for [17]. amidoximes was demonstrated. This zwitterion or aminonitrone was identified via FT-IR by the 1 presence of a mediumTable to strong 1. Infrared band bands at 1690 in solid cm −andassociated liquid phases to theof amidoximes. amidoxime C=N stretching at 1 1656 cm− . The main aminonitrone and amidoxime IR bands are summarized in Table1[17]. Stretching Solid Phase Stretching Liquid Phase a Functions Table 1. Infrared bands in solid and(cm liquid−1) phases of amidoximes. (cm−1)

OH - 1 3620 a 1 Functions Stretching Solid Phase (cm− ) Stretching Liquid Phase (cm− ) NH2 3400 and 3500 (sh) OH - 3620 NH2 scissor 1575–1620 NH 3400 and 3500 (sh) AmidoximeAmidoxime form form Associated2 NH scissor 1575–1620 OH2 2500 and 3300 (br) Associated OH and NH2 2500 and 3300 (br) and NH2 C=NC=N 1650–1670 1650–1670 (vs) (vs) + AminonitroneAminonitrone form C=N (H) 1690 (m – s) - a C=N+(H) 1690 (m – s) - liquidform phase stretching is performed in chloroform; sh: sharp, br: broad, vs: very sharp, m: medium, s: strong. a liquid phase stretching is performed in chloroform; sh: sharp, br: broad, vs: very sharp, m: medium, s: strong. Recent theoretical and experimental studies show that the most stable and dominant form is the Z-amidoximeRecent theoretical [15,16,18]. and This experimental isomer is more studies stable show than that the the iminohydroxylamine, most stable and dominant the aminonitrone form is the andZ-amidoxime the nitroso-amine, [15,16,18]. the This latter isomer being is more the less stable stable than [18 the]. However,iminohydroxylamine, according to the the aminonitrone most recent publishedand the nitroso-amine, work on that the topic latter [16], being three the amidoximes less stable isomers [18]. However, may coexist according due to theirto the close most relative recent energies:published theworkZ-amidoxime on that topic as [16], the three most amidoximes stable form isomers in both may protic coexist and aproticdue to their solvents close with relative the Zenergies:-aminonitrone the Z-amidoxime and the E-amino as the oxime most as stable the minor form forms.in both These protic theoretical and aprotic studies solvents were with conducted the Z- onaminonitrone two compounds, and the benzamidoxime E-amino oxime and as acetamidoxime. the minor forms.Z-aminotrone These theoretical and E -amidoximestudies were are conducted the most energeticallyon two compounds, stable after benzamidoxime the dominant and form acetamidoxime.Z-amidoxime: Z for-aminotrone acetamidoxime, and E the-amidoxime relative energies are the ofmost these energetically two tautomers stable are after of 3.0 the kcal dominant/mol and form 3.5 kcal Z-amidoxime:/mol, respectively, for acetamidoxime, while for benzamidoxime the relative theyenergies are ofof 4.5 these kcal /twomol andtautomers 5.4 kcal are/mol, of respectively. 3.0 kcal/mol The and other 3.5 tautomers,kcal/mol, Erespectively,-aminonitrone while and for all iminohydroxylaminebenzamidoxime they isomersare of 4.5 are lesskcal/mol energetically and 5.4 favorablekcal/mol, since respectively. their relative The energiesother tautomers, were higher E- thanaminonitrone 8.5 kcal/mol and in all the iminohydroxylamine case of acetoxime and isomers of 9.8 kcalare /lessmol energetically for benzamidoxime. favorable The since nitroso-amine their relative is alwaysenergies the were less energeticallyhigher than stable 8.5 isomerkcal/mol (∆ Gin 30the kcal case/mol). of Theacetoxime other tautomers and of show9.8 kcal/mol stabilities for in ≈ betweenbenzamidoxime. the tautomers The nitroso-amine mentioned above, is always the iminohydroxylamine the less energetically exhibiting stable isomer an intermediate (ΔG ≈ 30 kcal/mol). stability withThe ∆otherG 10–13 tautomers kcal/mol show (Figure stabilities4)[16,18]. in between the tautomers mentioned above, the iminohydroxylamine≈ exhibiting an intermediate stability with ΔG ≈ 10–13 kcal/mol (Figure 4) [16,18].

FigureFigure 4.4. Summary of the stability ofof amidoximeamidoxime isomers.isomers.

Molecules 2019, 24, x 4 of 18 Molecules 2019, 24, 2470 4 of 19 Oximes tautomers were also studied and three main tautomeric forms were identified, the oxime, the nitroneOximes tautomersand the nitroso were also compound studied and three(Figure main 5) tautomeric [19,20]. formsDepending were identified, on the the structure, oxime, other cyclic tautomersthe nitrone may and also the nitroso exist [19]. compound These (Figure various5)[ isomers19,20]. Depending may present on the differen structure,t biological other cyclic activities [20] but tautomersno data maycan alsobe existfound [19 ].in These the variousliterature isomers. The may first present identified different isomerization biological activities was [20 ]the but oxime– nitrone [21].no data Even can beif foundboth innitrone the literature. and nitroso The first tautom identifieders isomerization were identified was the to oxime–nitrone be less stable [21 ].than the Even if both nitrone and nitroso tautomers were identified to be less stable than the oxime form [22], oxime form [22], the nitrone form exhibits a higher reactivity than the oxime, especially in the nitrone form exhibits a higher reactivity than the oxime, especially in cyclooaddition reactions and cyclooadditionnucleophilic reactions addition and to unsaturated nucleophilic electrophiles addition [16 to,23 unsaturated]. The presence el ofectrophiles an electron donating[16,23]. groupThe presence of an electronon the oximedonating moiety group allows on to decreasethe oxime the energymoiety gap allows between to thedecrease oxime and the the energy nitrone gap form between and the oxime andstabilizes the thisnitrone latter, whichform facilitatesand stabilizes addition reactionsthis latter, [16]. However,which facilitates the oxime form addition is more reactivereactions [16]. However,than the the oxime nitrone form at high is pHmore [24 ].reactive than the nitrone at high pH [24].

R R R

N N N OH H O O Oxime Nitrone Nitroso compound

Figure 5. Tautomers of oximes. Figure 5. Tautomers of oximes. The oxime–nitrone tautomerism is the mostly studied in the literature and its mechanism was Theinvestigated. oxime–nitrone Recently, tautomerism Lopez et al. is demonstrated the mostly by studied theoretical in calculationsthe literature that and this isomerizationits mechanism was investigated.occurs Recently, via a bimolecular Lopez mechanismet al. demonstrated involving two by oximes theoretical or two calculations nitrones [23]. that Previous this studiesisomerization suggested that the oxime–nitrone tautomerism likely originated from a thermal 1,2-hydrogen shift and occurs via a bimolecular mechanism involving two oximes or two nitrones [23]. Previous studies a solvation effect [25–28]. suggested thatOximes the canoxime–nitrone also exist as stereoisomers tautomerism (Z/E forms).likely originated Numerous studies from showed a thermal that the 1,2-hydrogen (Z)-oxime shift and a solvationis the most effect stable [25–28]. configuration. This was proven by differential scanning calorimetry (DSC) studies in Oximeswhich can heating also and exist melting as stereoisomers of the E-oxime a ff(ordedZ/E forms). the Z-oxime. Numerous The oxime studies in its ( Eshowed) configuration that the (Z)- oxime ismay the bemost present stable with configuration. the Z-oxime but itThis represents was proven the minor by specie differential [20,25]. scanning calorimetry (DSC) studies in3. Synthesiswhich heating of Oximes and and melting Amidoximes of the E-oxime afforded the Z-oxime. The oxime in its (E) configuration may be present with the Z-oxime but it represents the minor specie [20,25]. According to the literature, amidoximes and oximes are compounds easily synthesized in high yields. Amidoximes are usually prepared from the corresponding nitriles and hydroxylamine while 3. Synthesisoximes of are Oximes generated and from Amidoximes the aldehydes /ketones and hydroxylamine.

According3.1. Synthesis to the of Amidoximes literature, amidoximes and oximes are compounds easily synthesized in high yields. Amidoximes are usually prepared from the corresponding nitriles and hydroxylamine while Amidoximes are compounds possessing an amino and a hydroxymino function on the same oximes arecarbon generated (Figure1 from)[ 7]. the The alde firsthydes/ketones synthesized amidoxime and hydroxylamine. is formamidoxime obtained in 1873 by Lossen and Schigerdecker [29,30] but the first chemical structure of amidoximes only appeared in 3.1. Synthesis1884 withof Amidoximes Tiemann’s work [30,31]. Many synthesis methods of amidoximes were explored but the most commonly used nowadays is the nucleophilic attack of hydroxylamine on a nitrile (vide infra). AmidoximesTables2–4 summarize are compounds all the processes possessing developed an for amin amidoximeso and synthesisa hydroxymino and reactions function are classified on the same carbon (Figureby the type1) [7]. of additivesThe first usedsynthesized [7,30]. The amid methodsoxime described is formamidoxime in Tables3 and obtained4 are scarcely in 1873 used by Lossen and Schigerdeckernowadays because [29,30] they but require the first more chemical sophisticated stru procedures.cture of amidoximes only appeared in 1884 with Tiemann’s workTable2 [30,31].shows that Many amidoximes synthesis can bemethods prepared of from amidoximes hydroxylamine were and nitrile,explored thioamide, but the most amidine hydrochloride, hydrazide imide, iminoether, imidoylbenzotriazole, and pyrazine derivatives. commonly used nowadays is the nucleophilic attack of hydroxylamine on a nitrile (vide infra). Tables The attack of hydroxylamine on nitriles is the mostly used method since Tiemann showed that mixing a 2–4 summarizenitrile with all hydroxylamine the processes hydrochloride developed and for sodium amidoximes carbonate insynthesis an alcohol producesand reactions the corresponding are classified by the type amidoximeof additives after used several [7,30]. hours The of heatingmethods at 60–80 described◦C[31]. in Via Tables this method, 3 and amidoximes4 are scarcely are generally used nowadays because preparedthey require in high more yield, sophisticated up to 98% (entry procedures. 1) [32]. Synthetic methods described in entries 2 and 3 Tableare 2 more shows scarcely that used amidoximes since the starting can be compounds prepared are from prepared hydroxylamine from nitriles [30 and]. In nitrile, some cases, thioamide, better results are obtained using thioamides than the nitriles [33]. The reaction of hydroxylamine amidine hydrochloride, hydrazide imide, iminoether, imidoylbenzotriazole, and pyrazine derivatives. The attack of hydroxylamine on nitriles is the mostly used method since Tiemann showed that mixing a nitrile with hydroxylamine hydrochloride and sodium carbonate in an alcohol produces the corresponding amidoxime after several hours of heating at 60–80 °C [31]. Via this method, amidoximes are generally prepared in high yield, up to 98% (entry 1) [32]. Synthetic methods described in entries 2 and 3 are more scarcely used since the starting compounds are prepared from nitriles [30]. In some cases, better results are obtained using thioamides than the nitriles [33]. The reaction of hydroxylamine with thioamides [30,33,34], amidines, hydrazide imides [30] or iminoethers [35], even if rarely used, usually affords the targeted amidoximes in yields varying from 60% to 100% (entries 2–4).

Molecules 2019, 24, 2470 5 of 19 with thioamides [30,33,34], amidines, hydrazide imides [30] or iminoethers [35], even if rarely used, usuallyMolecules affords 2019 the, 24, targetedx amidoximes in yields varying from 60% to 100% (entries 2–4). 6 of 18 Molecules 2019, 24, x 6 of 18 Molecules 2019, 24, x 6 of 18 Molecules 2019, 24, x TableTable 2. Amidoxime 2. Amidoxime syntheses syntheses using using hydroxylamine. hydroxylamine. 6 of 18 Molecules 2019, 24, x Table 2. Amidoxime syntheses using hydroxylamine. 6 of 18 Molecules 2019, Hydroxylamine24, x Table 2. Amidoxime syntheses using hydroxylamine. 6 of 18 EntryEntry Hydroxylamine Hydroxylamine ActionTable on 2. Amidoxime syntheses using hydroxylamine. Reaction Entry HydroxylamineAction on Table 2. Amidoxime syntheses using hydroxylamine. Entry Action on Table 2. Amidoxime syntheses using hydroxylamine. NH HydroxylamineAction on NH2OH 2 Entry Hydroxylamine RN NH OH NH2 Entry Action on 2 NH OH 11 Hydroxylamine nitrilenitrile RN NH2OH 2NR OH Entry Action on RN NH 1 Actionnitrile on NH2OH 2NR OH RN NH2 1 nitrile NH2OH R= Alkyl,NR OHAr RN NH2 1 nitrile NH2OH R= Alkyl,NR ArOH 1 nitrile RN R= Alkyl,NR OHAr 1 nitrile R= Alkyl,NR Ar 2 thioamide R= Alkyl, Ar 22 thioamide thioamide R= Alkyl, Ar 2 thioamide 2 thioamide 2 thioamide 2 thioamideamidine NH2OH NH amidine NH .HCl NH2OH 2 NH4Cl 3 hydrochloride or 2 NH amidine NH .HCl NH2OH 2 NH4Cl 3 hydrochloride or 2 NH amidinehydrazide hydrochlorideamidine imide or NH .HCl NH2OH N 2 NH4Cl 3 3 hydrochloride or NH 2 NH hydrazidehydrazideamidine imide imide NH .HCl NH2OH N OH2 NH4Cl 3 hydrochloride or NH 2 NH hydrazideamidine imide NH .HCl NH2OH N OH2 NH4Cl 3 hydrochloride or NH 2 NH hydrazide imide NH .HCl N OH2 NH4Cl 3 hydrochloride or NH 2 NH2OH hydrazide imide N OHNH NH O NH2OH 2 C2H5OH 4hydrazide iminoether imide N OHNH NH O NH2OH 2 C2H5OH 4 iminoether OHNH O NH2OH N 2 C2H5OH 4 iminoether NH NH O NH2OH N OH2 C2H5OH 44 iminoether iminoether NH NH O R NH2OH N OH2 R C2H5OH 4 iminoether NH NH O N R NHR OR N OH2N R C2H5OH 4 iminoether NH N 2 3 OHN R NHR OR ON R NH N 2 3 OHN NH N R1 NHR2OR3 R3 ON N R1 N R OHN R N R1 NHR2OR3 R3 O N R1 N N N R R2 N R N R1 NHR2OR3 R3 O N R1 N N R2 N N N R1 NHR2OR3 R3 O N R1 R= p-Tol,N N R = Bn R = H, R 2= H Imidoylbenzo- N1 R1 R32 O N3 R1 N R2 5 Imidoylbenzo- R= p-Tol,N NR1= BnMeR1 RR32= H, RN3= HBnR1 5 triazole R= p-Tol,N NR1= Bn R2= H, RR32= H Imidoylbenzo- R= pi-Bu,-Tol, R R11== Ph Me R2= H, R3= BnMe 5 triazole R= p-Tol,N R = Bn R = H, R 2= H Imidoylbenzo- R= ip4-MeOPh,-Bu,-Tol,N R R=1= Ph MeR = p-Tol R2= H,Me, R R3= =MeBn H triazole R= p-Tol, R1 = Bn1 R2= H, R3=3 H 5 Imidoylbenzo- R= pi-Bu,-Tol, R R=1= Ph Me R2= H, R3= BnMe R= 4-MeOPh,Ph, R =1 Ph R1= p-Tol R2= Me,H, R R3=3 =H H 55 Imidoylbenzo-triazoletriazole R= p-Tol,-Tol, 1 RR1= BnMe R2= H, R3= HBn Imidoylbenzo- R= i4-MeOPh,-Bu, R1=1 Ph R = p-Tol R2= H,Me, R R3= =Me H triazole R= Ph,i-Bu, R R1= =Ph Me1 R2= H, R3=3 HMe 5 R= pi-Bu,-Tol, R R11== Ph Me R2= H, R3= BnMe triazole R= 4-MeOPh,Ph, R =1 Ph R1= p-Tol R2= Me,H, R R3=3 =H H R= i2-Pyridyl,-Bu, R1 1= MeR = Ph R2= H, R3= MeBn R= i4-MeOPh,-Bu, R1= Ph R1 = p-Tol R2= H,Me, R 3R= =Me H R= Ph,i-Bu, R R1= =Ph Me1 R2= H, R3=3 HMe R= 2-Pyridyl,p-Tol, R1 = R 2-Furyl1= Ph R2= H,Me, R R3= =Bn H R= 4-MeOPh,Ph, R =1 Ph R1= p-Tol R2= Me,H, R R=3= H H R= i2-Pyridyl,-Bu, R11= MeR = Ph R2= H, R3= MeBn R= Ph,p-Tol, R R= 1Ph= 2-Furyl1 R2= H,Me, R R3O=3 =H H R OR= 2-Pyridyl,piR-Bu,-Tol, R1 R1== RMe 2-Furyl= Ph O R22= H,Me, R R33= =BnMe H 1 1 2 3O3 R Open chain OR= i2-Pyridyl,-Bu,R R1= MeR = PhN O R2= H,N R3= MeBn N R= p-Tol, R1= 2-Furyl1 R NH2OH R2= Me, R3O3= NHH R CO Me Open chain OR=N 2-Pyridyl,R CO Me R = Ph O R = H,N R = Bn 2 pyrazine N R= p-Tol, R21= 2-Furyl1 N N R NH OH R22= Me, 3R3= H Open chain H R N O 2 N O NHNR CO2Me 6 N OR=N p-Tol,CO R21Me= 2-Furyl R NH2OH R2= Me,N R3= H OH pyrazine R N N CO2Me N O NHN R CO2Me 6 derivativesOpenpyrazine chain and/or N O HN CO2Me N ON R NH OH N R N NH CO2Me 2 N ONHNHNROHCO2Me 6 derivativesOpen chain and/or N O NH CO2Me N O R NH OH 2 pyrrolopyrazinepyrazine N N N CO2Me 2 N NHOHCO Me derivativesOpen chain and/or N NH CO Me N NH R NHN2 2 6 pyrrolopyrazinepyrazine N 2 N CO MeNH2OH N R= CHNH3, BnOHCO Me Openderivatives chain pyrazine and/or N NH CO Me N NH 2 NHN2 2 6 pyrrolopyrazinepyrazine 2 N CO Me N R= CH3, BnOH derivatives and/or N HN N NH 2 NHN2 6 6 derivativespyrrolopyrazine and/or CO Me N R= CH3, BnOH derivatives and/or N N N NH 2 NH2 R= CH3, Bn The pyrrolopyrazinesecondpyrrolopyrazine synthetic process allowingN the preparation ofNH amidoximes involvesNH the2 reaction of pyrrolopyrazine R= CH3, Bn The second synthetic process allowing the preparation of amidoximes involves the reaction of ammoniaThe second or amines synthetic with oximinoethers,process allowing hydroxim the preparic acidsation or of nitric amidoximes oxides (TableinvolvesR= 3) CH [7,30].the3, Bn reactionThe first of ammoniaThe second or amines synthetic with oximinoethers,process allowing hydroxim the preparic acidsation or of nitric amidoximes oxides (Tableinvolves 3) [7,30].the reaction The first of ammoniaexampleThe describedsecond or amines synthetic in with the literatureoximinoethers, process allowing is the reactionhydroxim the prepar ofic ammonia acidsation or of nitric withamidoximes ethyloxides benzhydroximic (Table involves 3) [7,30].the reaction acid The forfirst of 8 exampleammoniaThe describedsecond or amines synthetic in with the literature oximinoethers,process allowing is the reactionhydroxim the prepar ofic ammonia acidsation or of nitric withamidoximes ethyloxides benzhydroximic (Tableinvolves 3) [7,30].the reaction acid The forfirst of 8 examplehammonia at 175 °C described or (Table amines 3, in entrywith the literature oximinoethers,1) [44]. This is the method reactionhydroxim is scarcely ofic ammonia acids used or nitricwithbut is ethyl oxidesof interest benzhydroximic (Table when 3) [7,30].using acid Theprimary for first 8 Theammoniaexampleh at 175 use °C ofdescribed or (Table the amines nitriles 3, in entrywith the and literature oximinoethers,1) [44]. hydroxylamine This is the method reactionhydroxim allows is scarcely ofic ammonia usuallyacids used or tonitricwithbut obtain is ethyloxides of interest the benzhydroximic (Table expected when 3) [7,30]. using amidoximes acid Theprimary forfirst 8 horexample at secondary 175 °C described (Table amines 3, in entry [30]. the literature1)The [44]. use This of is 2the methodequivalents reaction is scarcely of of ammonia amine used relative butwith is ethyl toof theinterest benzhydroximic hydroximic when using acid acid primarycauses for a8 in goodexamplehor at secondary yields175 °C described in(Table amines a reaction 3, in entry [30].the timeliterature The1) [44]. use varying This of is 2the methodequivalents from reaction of is 1scarcely of toof ammonia amine 48 hused depending relative withbut is ethyl toof the oninterest benzhydroximic hydroximic the substrates.when using acid acid causesprimary It is for the 8a orfasth at secondary dehydrohalogenation175 °C (Table amines 3, entry [30]. The1)followed [44]. use This of by 2 methodequivalentsa nucleophilic is scarcely of amineattack used relativeof butthe amineis toof theinterest on hydroximic the when intermediate using acid causesprimary nitrile a leadinghorfast at secondary method dehydrohalogenation175 °C (Table to amines prepare 3, entry [30]. amidoximes 1)Thefollowed [44]. use This of by using2 methodequivalentsa nucleophilic readily is scarcely of available amineattack used ofrelative nitriles butthe isamine toof as theinterest starting on hydroximic the when intermediate substrates using acid primarycauses [36 nitrile–38 a]. fastoxideor secondary dehydrohalogenation (Table 3, amines entry 2)[30]. [30]. Thefollowed use of by 2 equivalentsa nucleophilic of amineattack ofrelative the amine to the on hydroximic the intermediate acid causes nitrile a Hydroxylamineorfastoxide secondary dehydrohalogenation (Table hydrochloride3, amines entry 2)[30]. [30]. Thefollowed is associateduse of by 2 equivalentsa nucleophilic to bases of like amineattack triethylamine relativeof the amine to orthe on sodium hydroximic the intermediate carbonate acid causes (2nitrile to a 6 oxidefast dehydrohalogenation (Table 3, entry 2) [30]. followed by a nucleophilic attack of the amine on the intermediate nitrile equivalents)fastoxide dehydrohalogenation (TableTable that allow3, 3. entry Reaction the 2) in [30]. of situ ammoniafollowed generation andby aamines nucleophilic of hydroxylamine. with oximinoethers attack of The the and addition amine hydroximic on of the hydroxylamine acid intermediate chlorides. cannitrile be oxide (TableTable 3, 3. entryReaction 2) [30].of ammonia and amines with oximinoethers and hydroximic acid chlorides. conductedoxide (Table at room 3, temperatureentry 2) [30]. but is usually performed in refluxing ethanol or methanol to decrease Entry Table Ammonia 3. Reaction and Amine of ammonia Action onand amines with oximinoethers and hydroximic acid chlorides. the reactionEntry Table Ammonia time 3. [36 Reaction, 37and]. Amine Aromatic of ammonia Action amidoximes onand amines with are oximinoethers obtained in and higher hydroximic yields acid than chlorides. aliphatic ones. Entry AmmoniaTable 3. Reaction and Amine of ammonia Action onand amines with oximinoethers and hydroximic acid chlorides. Table 3. Reaction of ammonia and amines with oximinoethersNH3 and hydroximic acid chlorides. Nevertheless,Entry Ammonia it is still and possible Amine to Action improve on the yield by adding an excess of hydroxylamine.NH O NH3 2 C2H5OH Entry1 Ammoniaoximinoether and Amine Action on NH NH TheEntry use Ammonia of an aqueousand Amine solution Action on of hydroxylamineO has also3 been reported. In2 thisC2H case,5OH 1 oximinoether NH NH2 C H OH N O 3 N 2 5 1 oximinoether NH OHNH2 C H OH a base is not required and the reaction time is generallyN OOH shorter3 than when usingN hydroxylamine2 5 1 oximinoether NH OHNH2 N OHO 3 N C2H5OH hydrochloride1 [38,39]oximinoether. This method has been demonstrated to be of interest for the efficientOHNH2 preparationC H OH N OOH N 2 5 1 oximinoether NH3 OH N OH N NH of amidoximes starting from aliphatic nitriles. Cl NH3 N OH 2 2 hydroximic acid chlorides N OH NH NH OH Cl 3 OH 2 2 hydroximic acid chlorides NH NH2 N Cl 3 N 2 hydroximic acid chlorides NH OHNH2 N ClOH 3 N 2 hydroximic acid chlorides NH OHNH2 N OHCl 3 N 2 hydroximic acid chlorides OHNH2 2 hydroximic acid chlorides N ClOH N OH N OH N OH N OH N OH OH Molecules 2019, 24, x 6 of 18 Molecules 2019, 24, x 6 of 18 Table 2. Amidoxime syntheses using hydroxylamine. Table 2. Amidoxime syntheses using hydroxylamine. Hydroxylamine Entry Hydroxylamine Entry Action on Action on NH NH2OH 2 RN NH NH2OH 2 OH 1 nitrile RN NR OH 1 nitrile NR R= Alkyl, Ar R= Alkyl, Ar

2 thioamide 2 thioamide

amidine NH2OH NH amidine NH .HCl NH2OH 2 NH4Cl 3 hydrochloride or 2 NH NH .HCl 2 NH4Cl 3 hydrochloridehydrazide imide or 2 NH N hydrazide imide N OH NH OH

NH2OH NH O NH2OH 2 C2H5OH 4 iminoether NH 4 iminoether O 2 C2H5OH N Molecules 2019, 24, 2470 NH OH 6 of 19 NH N R OH R N R NHR OR N R N 2 3 N NHR2OR3 O Recently, Ranjbar-Karimi et al. synthesizedN a seriesR1 of amidoximes usingR3 O hydroxylamineN R1 and N R1 R3 N R1 nitriles via a solvent free method under ultrasonicN N irradiation. The reaction proceedsR2 in short time and N N R2 allows the productionImidoylbenzo- of amidoximes in highR= p yields-Tol, R1= (70–85%)Bn [40]. R2= H, R3= H 5 Imidoylbenzo- R= p-Tol, R1= BnMe R2= H, R3= HBn Finally,5 the ring-openingtriazole of heterocyclesR= p-Tol, using R = Me hydroxylamine wasR also= H, R demonstrated= Bn to be triazole R= i-Bu, R11= Ph R2= H, R3= Me of interest for the preparation of amidoximes.R= i4-MeOPh,-Bu, R1 One= Ph R1=of p-Tol the most recent methodsR2= H,Me, R R3=3 =Me H was developed R= 4-MeOPh,Ph, R = Ph R = p-Tol R = Me,H, R R= =H H by Katritzky et al. by using imidoylbenzotriazoles1 and1 hydroxylamine as2 starting3 3 reagents under R= Ph,i-Bu, R R1=1 =Ph Me R2= H, R3= HMe R= i-Bu, R = Me R = H, R = Me microwave irradiation (Table2, entry 5). ThisR= 2-Pyridyl, method1 R1= Ph allows the fast preparationR2= H, R3= Bn of amidoximes R= 2-Pyridyl,p-Tol, R1= R 2-Furyl1= Ph R2= H,Me, R R3=3 =Bn H (reaction time of 5–15 min) and in good yieldsR= p-Tol, (65–81%) R = 2-Furyl [41]. HydroxylamineR = Me, was R = alsoH used for the O R 1 O 2 O3 R R N O R synthesis of pyrazine-basedOpen chain amidoximesN fromO open chainN pyrazineO R derivativesNH OH or their pyrrolopyrazine 2 N NH CO2Me Openpyrazine chain N N CO2Me N N R NH OH tautomers. The reaction was demonstratedH to occur either via the attack2 of hydroxylamineNHN CO2Me on the 6 pyrazine N CO2Me N CO Me N OH 6 derivatives and/or N H N 2 N nitrile or the pyrrolidine ring. These reactionsN gave amidoximesN NH inCO2 yieldsMe rangingN fromNH OH 63–93% after derivativespyrrolopyrazine and/or N 2 N NH NH2 18 h (Table2, entrypyrrolopyrazine 6) [42,43]. R= CH3, Bn The second synthetic process allowing the preparation of amidoximes involvesR= CH3, Bn the reaction of ammoniaThe or second amines synthetic with oximinoethers, process allowing hydroximic the prepar acidsation orof nitricamidoximes oxides involves (Table3)[ the7, 30reaction]. The of first The second synthetic process allowing the preparation of amidoximes involves the reaction of exampleammonia described or amines in the with literature oximinoethers, is the reaction hydroxim ofic ammonia acids or withnitric ethyl oxides benzhydroximic (Table 3) [7,30]. acid The forfirst 8 h ammonia or amines with oximinoethers, hydroximic acids or nitric oxides (Table 3) [7,30]. The first at 175exampleC (Table described3, entry in 1)the [ literature44]. This methodis the reaction is scarcely of ammonia used but with isof ethyl interest benzhydroximic when using acid primary for 8 or example◦ described in the literature is the reaction of ammonia with ethyl benzhydroximic acid for 8 h at 175 °C (Table 3, entry 1) [44]. This method is scarcely used but is of interest when using primary secondaryh at 175 °C amines (Table [30 3,]. entry The 1) use [44]. of 2This equivalents method is of scarcely amine relativeused but to is theof interest hydroximic when acid using causes primary a fast or secondary amines [30]. The use of 2 equivalents of amine relative to the hydroximic acid causes a dehydrohalogenationor secondary amines followed [30]. The byuse a of nucleophilic 2 equivalents attack of amine of the relative amine to on the the hydroximic intermediate acid nitrile causes oxide a fast dehydrohalogenation followed by a nucleophilic attack of the amine on the intermediate nitrile (Tablefast3 dehydrohalogenation, entry 2) [30]. followed by a nucleophilic attack of the amine on the intermediate nitrile oxide (Table 3, entry 2) [30]. Moleculesoxide 2019(Table, 24, 3,x entry 2) [30]. 7 of 18 Molecules 2019Table, 24 3., x Reaction of ammonia and amines with oximinoethers and hydroximic acid chlorides. 7 of 18 Table 3. Reaction of ammonia and amines with oximinoethers and hydroximic acid chlorides. SomeTable examples 3. Reaction of reactions of ammonia rarely and aminesdescribed with inoximinoethers the literature and but hydroximic allowing acid the chlorides. preparation of EntrySome Ammonia examples and of Amine reactions Action rarely on described in the literature Reaction but allowing the preparation of amidoximesEntry Ammonia are described and Amine in ActionTable 4.on The reduction of benzonitrosolic acid with hydrogen sulfide Entry Ammonia and Amine Action on amidoximeswas reported are in 1906described by Wiel in andTable and 4. BauerThe reduction (entry 1) of[45]. benzonitrosolic acid with hydrogen sulfide NH3 was reported in 1906 by Wieland and Bauer (entry 1) [45]. NH2 C H OH Some reducing agents are able to open nitrogenO containingNH3 heterocycles like 1,2,4-oxadiazoles,2 5 11 oximinoetheroximinoether NH Some reducing agents are able to open nitrogenO containing heterocycles like 1,2,4-oxadiazoles,2 C2H5OH Δ′-1,2,4-oxadiazoles,1 oximinoether 1-alkoxyadenines and 1,2,5-oxadiazoles [7,30]. The reactionN of lithium N OH Δ′-1,2,4-oxadiazoles, 1-alkoxyadenines and 1,2,5-oxadiazolesN OH [7,30]. The reactionN of lithium aluminum hydride (LiAlH4) with Δ′-1,2,4-oxadiazolesOH allows the break of the C-O bondOH to give N- aluminum hydride (LiAlH4) with Δ′-1,2,4-oxadiazoles allows the break of the C-O bond to give N- substituted amidoximes in 70% to 72% yield (entry 2) [46]. NH3 NH substituted2 amidoximes hydroximic acid in 70% chlorides to 72% yield (entry 2) [46].Cl NH3 2 Finally, 1,2,4-oxadiazoles can also be transformedCl into amidoximes (yield of 75%–85%)NH2 by 2Finally,2 hydroximic hydroximic1,2,4-oxadiazoles acid acid chlorides chlorides can also be transformed into amidoximes (yield of 75%–85%)N by reaction with aqueous NaOH [47]. Amidoximes wereN obtained in lower yields (35%–63%)OH after reaction with aqueous NaOH [47]. Amidoximes wereN OHobtained in lower yields (35%–63%)N after passing 1-alkoxyadenine derivatives through AmberliteOH IRA 402 column and heating theOH eluate at passing 1-alkoxyadenine derivatives through Amberlite IRA 402 column and heating the eluate at 30–40°C for 7–48 h [48]. 30–40°C for 7–48 h [48]. Table 4. Miscellaneous reactions allowing the preparation of amidoximes. Table 4. Miscellaneous reactions allowing the preparation of amidoximes. Table 4. Miscellaneous reactions allowing the preparation of amidoximes. Entry Method Reaction Entry Method Entry Method ReductionReduction of of nitrosolic nitrosolic 2H2S NH2 Reduction of nitrosolic N 2H2S H2O 2S 11 acidsacids and and related related O NH2 1 acids and related N H2O 2S compoundscompounds N O N compounds OH N OH N OH OH N O NOH N LiAlH O R 4 NOH LiAlH R2 N R NO2 4 N R2 N NO2 NH RingRing opening opening of nitrogen- of 2 Ring opening of nitrogen- R1 H 2 containingnitrogen-containing heterocycles R1 containing heterocycles R= COOEt, R1= Cl R2= (CH2)2NH2 heterocycles R=R= COOEt,COOEt, RR11== ClNO2 RR22== (CH(CH22))22NHNH22 R=R= COOEt,NO2, R1 R= 1NO= NO2 2 RR22== (CHMe 2)2NH2 R= NO2, R1= NO2 R2= Me 3.2. Synthesis of Oximes 3.2. Synthesis of Oximes SomeAn oxime examples is a compound of reactions belonging rarely describedto imines infamily the literature(RR′C = NOH). but allowing If R is an the alkyl preparation or an aryl of An oxime is a compound belonging to imines family (RR′C = NOH). If R is an alkyl or an aryl amidoximesgroup, R′ may are be described a hydrogen in Table atom4. The(aldoxime) reduction or ofan benzonitrosolicalkyl/aryl group acid (ketoxime) with hydrogen (Figure sulfide 1). These was group, R′ may be a hydrogen atom (aldoxime) or an alkyl/aryl group (ketoxime) (Figure 1). These reportedcompounds in 1906 are usually by Wieland synthesized and Bauer by (entrythe addition 1) [45]. of hydroxylamine on an aldehyde or a ketone compounds are usually synthesized by the addition of hydroxylamine on an aldehyde or a ketone [25,49,50]. The preparation of oximes is extensively described in the literature. Some improvements [25,49,50]. The preparation of oximes is extensively described in the literature. Some improvements were described to enhance the yields and decrease the by-products formation. In 1999, Hajipour et were described to enhance the yields and decrease the by-products formation. In 1999, Hajipour et al. reported the oximation of aldehydes and ketones using hydroxylamine hydrochloride under al.microwave reported irradiationthe oximation in solvent of aldehydes free conditions. and ketones The usingprocess hydroxylamine was demonstrated hydrochloride to be of higherunder microwave irradiation in solvent free conditions. The process was demonstrated to be of higher efficiency for the synthesis of aldoximes using hydroxylamine hydrochloride and silica gel (yields efficiency for the synthesis of aldoximes using hydroxylamine hydrochloride and silica gel (yields higher than 76% and reaction time of 4 min) [51]. A similar solvent free method was reported in 2002 higher than 76% and reaction time of 4 min) [51]. A similar solvent free method was reported in 2002 using hydroxylamine hydrochloride and zinc oxide giving yield of 80-98% and reaction time varying using hydroxylamine hydrochloride and zinc oxide giving yield of 80-98% and reaction time varying between 5 and 15 min at 140–170°C [52]. between 5 and 15 min at 140–170°C [52]. Recently, Li et al. reported an efficient synthesis of oximes under sonication (yields ranging 51 Recently, Li et al. reported an efficient synthesis of oximes under sonication (yields ranging 51 to 99% and short reaction times). The reaction is conducted in ethanol in the presence of anhydrous tosodium 99% and sulfate short [53]. reaction times). The reaction is conducted in ethanol in the presence of anhydrous sodium sulfate [53]. Oximes can also be synthesized by the oxidation of aliphatic amines using m-CPBA. This Oximes can also be synthesized by the oxidation of aliphatic amines using m-CPBA. This reaction gave very high yields (>90%) in 20 min and at room temperature [54]. reaction gave very high yields (>90%) in 20 min and at room temperature [54]. 4. Oxidation of Amidoximes/Oximes and NO Release 4. Oxidation of Amidoximes/Oximes and NO Release During many years, NO was considered to present no beneficial biological effects and to be even During many years, NO was considered to present no beneficial biological effects and to be even toxic due to its presence in polluted environments [55]. In the 1980s, it was observed that a molecule

toxicreleased due fromto its the presence endothelium in polluted is responsible environments of the [55]. vasodilatorsIn the 1980s, effects it was and observed it was later that identified a molecule as released from the endothelium is responsible of the vasodilators effects and it was later identified as NO. Since, numerous studies on NO showed many biological benefits including its important role in NO. Since, numerous studies on NO showed many biological benefits including its important role in vasodilation and blood pressure reduction [56]. For this reason, amidoximes and oximes were vasodilation and blood pressure reduction [56]. For this reason, amidoximes and oximes were studied for their capacity of NO release. studied for their capacity of NO release. 4.1. Oxidation by Chemicals and Biomimetics 4.1. Oxidation by Chemicals and Biomimetics Molecules 2019, 24, 2470 7 of 19

Some reducing agents are able to open nitrogen containing heterocycles like 1,2,4-oxadiazoles, ∆0-1,2,4-oxadiazoles, 1-alkoxyadenines and 1,2,5-oxadiazoles [7,30]. The reaction of lithium aluminum hydride (LiAlH4) with ∆0-1,2,4-oxadiazoles allows the break of the C-O bond to give N-substituted amidoximes in 70% to 72% yield (entry 2) [46]. Finally, 1,2,4-oxadiazoles can also be transformed into amidoximes (yield of 75–85%) by reaction with aqueous NaOH [47]. Amidoximes were obtained in lower yields (35–63%) after passing 1-alkoxyadenine derivatives through Amberlite IRA 402 column and heating the eluate at 30–40◦C for 7–48 h [48].

3.2. Synthesis of Oximes

An oxime is a compound belonging to imines family (RR0C = NOH). If R is an alkyl or an aryl group, R0 may be a hydrogen atom (aldoxime) or an alkyl/aryl group (ketoxime) (Figure1). These compounds are usually synthesized by the addition of hydroxylamine on an aldehyde or a ketone [25,49,50]. The preparation of oximes is extensively described in the literature. Some improvements were described to enhance the yields and decrease the by-products formation. In 1999, Hajipour et al. reported the oximation of aldehydes and ketones using hydroxylamine hydrochloride under microwave irradiation in solvent free conditions. The process was demonstrated to be of higher efficiency for the synthesis of aldoximes using hydroxylamine hydrochloride and silica gel (yields higher than 76% and reaction time of 4 min) [51]. A similar solvent free method was reported in 2002 using hydroxylamine hydrochloride and zinc oxide giving yield of 80-98% and reaction time varying between 5 and 15 min at 140–170◦C[52]. Recently, Li et al. reported an efficient synthesis of oximes under sonication (yields ranging 51 to 99% and short reaction times). The reaction is conducted in ethanol in the presence of anhydrous sodium sulfate [53]. Oximes can also be synthesized by the oxidation of aliphatic amines using m-CPBA. This reaction gave very high yields (>90%) in 20 min and at room temperature [54].

4. Oxidation of Amidoximes/Oximes and NO Release During many years, NO was considered to present no beneficial biological effects and to be even toxic due to its presence in polluted environments [55]. In the 1980s, it was observed that a molecule released from the endothelium is responsible of the vasodilators effects and it was later identified as NO. Since, numerous studies on NO showed many biological benefits including its important role in vasodilation and blood pressure reduction [56]. For this reason, amidoximes and oximes were studied for their capacity of NO release.

4.1. Oxidation by Chemicals and Biomimetics Since the NO production in the human body originates from the oxidation of l-arginine by NOS, this oxidation route and the factors affecting the oxidation were investigated. In 1998, Koikov et al. studied the oxidation of three series of compounds including oximes and amidoximes at a concentration of 2 10 4 M with K Fe[(CN) ] at pH 12 [57]. Under these conditions, oximes were not able of releasing × − 3 6 NO and this phenomenon was explained by the acceptor or donor properties of the substituents (hydroxyphenyl and pyridine rings) and by the acidity of the oxime functions. However, many tested amidoximes showed the capacity to release NO in the presence of K3Fe[(CN)6] and methyl and phenyl amidoximes released 25% and 10% of NO, respectively. It was observed that replacing the phenyl ring by a pyridine ring allows to increase twice the amount of released NO and that the amidoximes exhibit quite a similar potential of NO release than methylamidoxime. The structures of these amidoximes are shown in Figure6. The most important release was observed for the pyridine-2,6-diamidoxime for which the amount of released NO reached up to 40%. Benzonitrile was also identified as the major product present after the oxidation of benzamidoxime. MoleculesMolecules 20192019,, 2424,, xx 88 ofof 1818

SinceSince thethe NONO productionproduction inin thethe humanhuman bodybody originatesoriginates fromfrom thethe oxidationoxidation ofof LL-arginine-arginine byby NOS,NOS, thisthis oxidationoxidation routeroute andand thethe factorsfactors affectingaffecting thethe oxidationoxidation werewere investigated.investigated. InIn 1998,1998, KoikovKoikov etet al.al. studiedstudied thethe oxidationoxidation ofof threethree seriesseries ofof compoundscompounds includingincluding oximesoximes andand amidoximesamidoximes atat aa −4 concentrationconcentration ofof 22 ×× 1010−4 MM withwith KK33Fe[(CN)Fe[(CN)66]] atat pHpH 1212 [57].[57]. UnderUnder thesethese conditions,conditions, oximesoximes werewere notnot ableable ofof releasingreleasing NONO andand thisthis phenomenonphenomenon waswas explexplainedained byby thethe acceptoracceptor oror donordonor propertiesproperties ofof thethe substituentssubstituents (hydroxyphenyl(hydroxyphenyl andand pyridinepyridine rings)rings) anandd byby thethe acidityacidity ofof thethe oximeoxime functions.functions. However,However, manymany testedtested amidoximesamidoximes showedshowed thethe capacitycapacity toto releaserelease NONO inin thethe presencepresence ofof KK33Fe[(CN)Fe[(CN)66]] andand methylmethyl andand phenylphenyl amidoximesamidoximes releasedreleased 25%25% andand 10%10% ofof NO,NO, respectively.respectively. ItIt waswas observedobserved thatthat replacingreplacing thethe phenylphenyl ringring byby aa pyridinepyridine ringring allowsallows toto increaseincrease twicetwice thethe amountamount ofof releasedreleased NONO andand thatthat thethe amidoximesamidoximes exhibitexhibit quitequite aa similarsimilar potepotentialntial ofof NONO releaserelease thanthan methylamidoxime.methylamidoxime. TheThe structuresstructures ofof thesethese amidoximesamidoximes areare shownshown inin FigureFigure 6.6. TheThe mostmost importantimportant releaserelease waswas observedobserved forfor theMoleculesthe pyridine-2,6-diamidoximepyridine-2,6-diamidoxime2019, 24, 2470 forfor whwhichich thethe amountamount ofof releasedreleased NONO reachedreached upup toto 40%.40%. BenzonitrileBenzonitrile8 of 19 waswas alsoalso identifiedidentified asas thethe majormajor productproduct prpresentesent afterafter thethe oxidationoxidation ofof benzamidoxime.benzamidoxime.

OHOH

HH2NNNN NH 2 NH22 H N H N H N NH H22N H22N H22N NH22 HOHO NN NN NN NN NN NN NN HOHO HOHO HOHO OHOH NN

MethylamidoximeMethylamidoxime BenzamidoximeBenzamidoxime Pyridine-2-amidoximePyridine-2-amidoxime Pyridine-4-amidoximePyridine-4-amidoxime Pyridine-2,6-amidoxime Pyridine-2,6-amidoxime

Figure 6. Amidoximes releasing NO in the presence of K3Fe[(CN)6]. FigureFigure 6.6. AmidoximesAmidoximes releasingreleasing NONO inin thethe presencepresence ofof KK33Fe[(CN)Fe[(CN)66].]. To better understand the products formed during the oxidation of amidoximes, Vadon-Le Goff To better understand the products formed during the oxidation of amidoximes, Vadon-Le Goff et al.To reported better understand the use of various the products oxidants formed and biomimetic during the systemsoxidation to of study amidoximes, the reaction Vadon-Le products Goff as et al. reported the use of various oxidants and biomimetic systems to study the reaction products as etwell al. asreported the causes the use and of factors various aff oxidantsecting the and outcome biomimetic of the systems reaction to [study4]. The the authors reaction evaluated products the as well as the causes and factors affecting the outcome of the reaction [4]. The authors evaluated the wellpotential as the of causes NO release and factors of 4-chlorobenzamidoxime affecting the outcom ine of the the presence reaction of [4]. diff Theerent authors oxidants. evaluated Amides the or potential of NO release of 4-chlorobenzamidoxime in the presence of different oxidants. Amides or potentialnitriles were of NO identified release as of the 4-chlorobenzamidoxime main products but the in presence the presence of a dimeric of different product oxidants. in the mixture Amides was or nitriles were identified as the main products but the presence of a dimeric product in the mixture was nitrilesalso detected were identified (Figure7). as the main products but the presence of a dimeric product in the mixture was alsoalso detecteddetected (Figure(Figure 7).7). ClCl

H N H22N

NN OO

NHNH

ClCl

FigureFigure 7. 7. DimericDimeric product product obtained obtained fr fromfromom 4-chlorobenzamidoxime. 4-chlorobenzamidoxime.

It was demonstrated that with oxidants like Pb(OAc)4 and Ag2CO3, amidoximes are selectively ItIt waswas demonstrateddemonstrated thatthat withwith oxidantsoxidants likelike Pb(OAc)Pb(OAc)44 andand AgAg22COCO33,, amidoximesamidoximes areare selectivelyselectively oxidized into nitriles, while amides were selectively formed using oxidants capable of transferring one oxidizedoxidized intointo nitriles,nitriles, whilewhile amidesamides werewere selectivselectivelyely formedformed usingusing oxidantsoxidants capablecapable ofof transferringtransferring oxygen atom like H2O2, t-BuOOH or m-CPBA. Using m-CPBA, 4-chlorobenzamidoxime was oxidized oneone oxygenoxygen atomatom likelike HH22OO22,, t-t-BuOOHBuOOH oror mm-CPBA.-CPBA. UsingUsing mm-CPBA,-CPBA, 4-chlorobenzamidoxime4-chlorobenzamidoxime waswas into a mixture of dimeric products and amide, the latter being the major component. This oxidant, oxidizedoxidized intointo aa mixturemixture ofof dimericdimeric productsproducts andand amide,amide, thethe latterlatter beingbeing thethe majormajor component.component. ThisThis as well as t-BuOOH, associated with catalytic amounts of iron-porphyrin generates preferentially the oxidant,oxidant, asas wellwell asas t-t-BuOOH,BuOOH, associatedassociated withwith catalyticcatalytic amamountsounts ofof iron-porphyriniron-porphyrin generatesgenerates nitrile in less than 1 h (ca. 80% of the amidoxime oxidized) (Table5, lines 1–3). This likely originates preferentiallypreferentially thethe nitrilenitrile inin lessless thanthan 11 hh (ca.(ca. 80%80% ofof thethe amidoximeamidoxime oxidized)oxidized) (Table(Table 5,5, lineslines 1–3).1–3). ThisThis from the formation of highly reactive iron-oxo species which oxidize the amidoxime into the nitrile. likelylikely originatesoriginates fromfrom thethe formationformation ofof highlyhighly reacreactivetive iron-oxoiron-oxo speciesspecies whichwhich oxidizeoxidize thethe amidoximeamidoxime This result is in accordance with those described in the literature related to the oxidation of amidoximes intointo thethe nitrile.nitrile. ThisThis resultresult isis inin accordanceaccordance wiwithth thosethose describeddescribed inin thethe literatureliterature relatedrelated toto thethe by hemoproteins. Horseradish peroxidase, able of generating iron-oxo species in the presence of H O , oxidationoxidation ofof amidoximesamidoximes byby hemoproteins.hemoproteins. HorserHorseradishadish peroxidase,peroxidase, ableable ofof generatinggenerating iron-oxoiron-oxo2 2 oxidizes amidoximes to nitriles and a dimeric product. On the other hand, the oxidation by CYP450 speciesspecies inin thethe presencepresence ofof HH22OO22,, oxidizes oxidizes amidoximesamidoximes toto nitrilesnitriles andand aa dimericdimeric product.product. OnOn thethe otherother generates exclusively the amide product instead of the nitrile. This was explained by the presence of hand,hand, thethe oxidationoxidation byby CYP450CYP450 generatesgenerates exclusivelyexclusively thethe amideamide productproduct insteadinstead ofof thethe nitrile.nitrile. ThisThis the superoxide O2 − radical anion or of a protein-metal-O− 2 complex instead of the presence of the waswas explainedexplained byby thethe• presencepresence ofof thethe superoxidesuperoxide OO22••− radicalradical anionanion oror ofof aa protein-metal-Oprotein-metal-O22 complex complex iron-oxo intermediates (see Section 4.2 for the oxidation by CYP450). insteadinstead ofof thethe presencepresence ofof thethe iron-oxoiron-oxo intermediaintermediatestes (see(see sectionsection 4.24.2 forfor thethe oxidationoxidation byby CYP450).CYP450).

Table 5. Summary of the major oxidation products after amidoxime reaction with different chemical and biomimetic oxidants.

Major Oxidation Products Entry Amide Nitrile 1 Monoelectronic oxidants √ 2 O2 atom donors √ 3 O2 atom donors + iron-porphyrin catalyst √ 4 Photooxygenation of amidoximates √ 5 IBX √ 6 IBX/TEAB √ √ Major product formed. Molecules 2019, 24, x 9 of 18

Table 5. Summary of the major oxidation products after amidoxime reaction with different chemical and biomimetic oxidants.

Major Oxidation Products Entry Amide Nitrile 1 Monoelectronic oxidants √ 2 O2 atom donors √ 3 O2 atom donors + iron-porphyrin catalyst √ Photooxygenation 4 √ of amidoximates 5 IBX √ Molecules 2019, 24, 24706 IBX/TEAB √ 9 of 19 √ Major product formed. Amidoximes and oximes can also be oxidized via the amidoximate/oximate anions in the presence Amidoximes and oximes can also be oxidized via the amidoximate/oximate anions1 in the of singlet oxygen [58]. The authors demonstrate that amidoximes and oximes are inert to O2 but oncepresence converted of singlet to amidoximates oxygen [58]. and The under authors photooxygenation, demonstrate that amidoximes amidoximes can and be oxidizedoximes are into inert the to 1O2 but once converted to amidoximates and under photooxygenation, amidoximes can1 be oxidized corresponding amides along with nitriles as minor products (Table5, entry 4). The use of O2 is similar 1 tointo the oxidationthe corresponding of N-hydroxyguanidines amides along with by nitriles the NOS as minor and clarifies products the (Table biological 5, entry oxidation 4). The use routes of O2 (Figureis similar8, red to part). the oxidation of N-hydroxyguanidines by the NOS and clarifies the biological oxidation routesTo better (Figure understand 8, red part). the oxidation process of amidoximes, oxidants like 2-iodobenzoic acid (IBX) and theTo IBX better/tetraethylammonium understand the oxidation bromide process (TEAB) of combination amidoximes, were oxidants also used like [ 122-iodobenzoic]. The authors acid demonstrate(IBX) and thatthe IBX/tetraethylammonium IBX can selectively oxidize bromide benzamidoxime (TEAB) combination (Figure8, blue were part) also into used amide [12]. (best The yieldauthors of 83% demonstrate using an amidoxime:IBXthat IBX can selectively ratio of oxidize 1:1 and benzamidoxime only 10% of the (Figure nitrile). 8, blue This part) method into wasamide extended(best yield to variousof 83% using amidoximes an amidoxime:IBX and similar ratio results of 1:1 were and obtained.only 10% of Nevertheless, the nitrile). This the method use of an was amidoxime:IBX:TEABextended to various molar amidoximes ratio of 1:2:2and gavesimilar 90% result of thes were nitrile obtained. and only 5%Nevertheless, of the amide. the By use using of an thisamidoxime:IBX:TEAB ratio with a series of molar amidoximes, ratio of similar 1:2:2 gave results 90% were of the obtained nitrile and by theonly authors 5% of the (Table amide.5, entries By using 5 andthis 6). ratio with a series of amidoximes, similar results were obtained by the authors (Table 5, entries 5 and 6).

Figure 8. Structures of amidoximes able to be oxidized after photoxygenation or by treatment 2-iodobenzoicFigure 8. Structures acid or IBX of/ tetraethylammoniumamidoximes able to be bromide. oxidized after photoxygenation or by treatment 2- iodobenzoic acid or IBX/tetraethylammonium bromide. 4.2. Biological Pathways of Amidoximes and Oximes Oxidation 4.2.As Biological it is well Pathways known, NO of Amidoximes is synthesized andin Oximes vivo by Oxidation the NOS enzymes. In recent years, many scientists got interested in finding new ways to oxidize amidoximes and oximes in order to increase the NO concentration in the organism. A few studies demonstrated that C=N-OH moieties present in compounds like amidoximes and oximes can be oxidized by CYP450 enzymes [59,60]. In 1998, a study showed the key role of CYP450 in the oxidation of amidoximes, oximes and N-hydroxyguanidines along with their oxidation products [5]. In the presence of rat liver microsomes, NADPH and O2, – amidoximes and oximes can be oxidized and release NO and NO-related aerobic products like NO2 and NO3−. The presence of both NADPH and O2 and of the active microsomes was demonstrated to be essential for the oxidation, indicating that this reaction is enzymatic. Moreover, the authors demonstrated that the CYP450 present in the microsomes are responsible for this reaction by using either the CYP450 inhibitor Miconazole which caused the inhibition by ca. 80–90% of the reaction or Dexomethasone (DEX), a CYP450 inducer, treated microsomes. The oxidation of various amidoximes Molecules 2019, 24, x 10 of 18

As it is well known, NO is synthesized in vivo by the NOS enzymes. In recent years, many scientists got interested in finding new ways to oxidize amidoximes and oximes in order to increase the NO concentration in the organism. A few studies demonstrated that C=N-OH moieties present in compounds like amidoximes and oximes can be oxidized by CYP450 enzymes [59,60]. In 1998, a study showed the key role of CYP450 in the oxidation of amidoximes, oximes and N-hydroxyguanidines along with their oxidation products [5]. In the presence of rat liver microsomes, NADPH and O2, amidoximes and oximes can be oxidized and release NO and NO-related aerobic products like NO2– and NO3−. The presence of both NADPH and O2 and of the active microsomes was demonstrated to be essential for the oxidation, indicating that this reaction is enzymatic. Moreover, the authors demonstrated that the CYP450 present in the microsomes are responsible for this reaction by using eitherMolecules the2019 CYP450, 24, 2470 inhibitor Miconazole which caused the inhibition by ca. 80%–90% of the reaction10 of 19 or Dexomethasone (DEX), a CYP450 inducer, treated microsomes. The oxidation of various amidoximes and oximes generates both NO2− and NO3−, especially in the presence of DEX-treated and oximes generates both NO and NO , especially in the presence of DEX-treated microsomes microsomes which boosts the oxidation.2− This3− release was always accompanied by the formation of which boosts the oxidation. This release was always accompanied by the formation of amides and amides and nitriles in the case of amidoximes and of ketones and nitroalkanes in the case of nitriles in the case of amidoximes and of ketones and nitroalkanes in the case of ketoximes. ketoximes. In 2004, another study used CYP450 to test the oxidation of the oximes. Hence, Mäntylä et al. In 2004, another study used CYP450 to test the oxidation of the oximes. Hence, Mäntylä et al. incubated buparvaquone–oxime and its derivatives with NADPH and either untreated rat liver incubated buparvaquone–oxime and its derivatives with NADPH and either untreated rat liver microsomes or treated ones with various CYP450 inducers. These buparvaquone’s prodrugs were microsomes or treated ones with various CYP450 inducers. These buparvaquone’s prodrugs were studied for their ability to be oxidized and releasing the corresponding buparvaquone alongside studied for their ability to be oxidized and- releasing the corresponding buparvaquone alongside NO NO which was quantified via the NO2 species produced [61]. All of the oximes were able to be which was quantified via the NO2- species produced [61]. All of the oximes were able to be oxidized oxidized in the presence of CYP450 and release buparvaquone bearing a C=O function effective against in the presence of CYP450 and release buparvaquone bearing a C=O function effective against leishmaniasis. The presence of NO was also believed to have a role against this disease. The solubility leishmaniasis. The presence of NO was also believed to have a role against this disease. The solubility of the oximes prodrugs was further improved by the synthesis of their corresponding phosphate of the oximes prodrugs was further improved by the synthesis of their corresponding phosphate prodrugs. These latter were able to release the corresponding oximes-buparvaquone [62]. prodrugs. These latter were able to release the corresponding oximes-buparvaquone [62]. Recently, we evaluated the capacity of mono- and bis-amidoximes to release NO by a Recently, we evaluated the capacity of mono- and bis-amidoximes to release NO by a CYP450- CYP450-mediated oxidation (Figure9)[ 38]. Amidoximes were also incubated with NADPH and mediated oxidation (Figure 9) [38]. Amidoximes were also incubated with NADPH and untreated untreated microsomes. Only aromatic mono-amidoximes showed an important NO release while the microsomes. Only aromatic mono-amidoximes showed an important NO release while the aliphatic aliphatic mono-amidoxime and the bis-amidoxime bearing both an aromatic and aliphatic amidoxime mono-amidoxime and the bis-amidoxime bearing both an aromatic and aliphatic amidoxime released released only small NO quantities. The inadequate size or shape of the latter compounds and/or the only small NO quantities. The inadequate size or shape of the latter compounds and/or the lower lower reactivity of the aliphatic amidoximes compared to aromatic ones hinders their metabolization reactivity of the aliphatic amidoximes compared to aromatic ones hinders their metabolization by rat by rat liver microsomes. It was of interest to determine if these amidoximes are able to release NO liver microsomes. It was of interest to determine if these amidoximes are able to release NO once once incubated with human cells not originating from the liver. For that purpose, these compounds incubated with human cells not originating from the liver. For that purpose, these compounds were were first demonstrated to be cytocompatible with human vascular smooth muscle cells (HVSMC) and first demonstrated to be cytocompatible with human vascular smooth muscle cells (HVSMC) and were later incubated with these cells for 1 h to evaluate their ability to release NO. This test showed were later incubated with these cells for 1 h to evaluate their ability to release NO. This test showed that all of the amidoximes are able to release NO and to increase the NO storage through nitrosothiol that all of the amidoximes are able to release NO and to increase the NO storage through nitrosothiol (RSNO) formation inside the cells. It is worth mentioning that the bis-amidoxime exhibited a high (RSNO) formation inside the cells. It is worth mentioning that the bis-amidoxime exhibited a high potential for the generation of RSNO, very close to that of the aromatic mono-amidoximes, but at a potential for the generation of RSNO, very close to that of the aromatic mono-amidoximes, but at a twice lower concentration. twice lower concentration.

Cl OH O

H2N H2N H2N N N N HO HO HO

O NH2 O NH2

N H2N N OH OH N HO Figure 9. Structures of tested mono- and bis-amidoximes for NO release on rat liver microsomes and Figure 9. Structures of tested mono- and bis-amidoximes for NO release on rat liver microsomes and human vascular smooth muscle cells. human vascular smooth muscle cells. Other reports focused on finding the capacity of the NOS in oxidizing amidoximes and oximes. – Acetoxime can be oxidized by CYP450 and NADPH in the presence of metal complexes into NO2 and reactive NO species [63]. However, this study clearly proved that acetoxime cannot be oxidized by the NOS II enzyme and cannot even inhibit its activity, which suggests a low affinity between NOS and this ketoxime. This demonstrates that the oxidation pathway of acetoxime in the cells involves only CYP450. In another study, four amidoximes were incubated with NOS I and II and NADPH and the NO formation was monitored by the Griess assay in order to study the amidoximes recognition by NOS [64]. All the amidoximes were inactive in the presence of NOS and did not show any NO release. Moreover, they are also very bad inhibitors of NOS I and II. The corresponding N-hydroxyguanidines analogs showed high affinity, indicating that the NOS better recognizes molecules bearing the –NH-C(R)=NH moiety than C=NOH. The latest study related to that topic was conducted in 2002 [65], and a series of N-hydroxyguanidines, amidoximes, ketoximes and aldoximes where tested for their NO release Molecules 2019, 24, 2470 11 of 19 capacity in the presence of recombinant NOS II. The presence of an unmodified N-hydroxyguanidine function is mandatory for the oxidation by the NOS. Thus, none of the amidoximes and oximes could be oxidized by this enzyme. As shown by these studies, CYP450 seems to be responsible of the oxidation of both amidoximes and oximes while NOS does not appear to have a role in these oxidations. As mentioned above, the oxidations by CYP450 afforded as major products amides in the case of amidoximes and ketones in the case of oximes alongside with the release of NO, nitrites and nitrates [63–65]. The mechanism of amidoximes and oximes oxidation by CYP450 that generates amides/ketones is explained by the formation of the superoxide radical anion (O ) which is a dissociation product of the CYP450-Fe(II)-O complex, 2•− 2 this latter was shown to be easily transformed to CYP420-Fe(II)-O2 during the oxidation [60,63–65]. The formation, even in small amounts, of a nitrile and nitroalkane mixture originates from the presence of an iron-oxo complex as it is the case for the biomimetic reactions generating nitriles. Many CYP450 isoforms have been identified as responsible of the oxidations of these products like CYP4501A1, CYP4502B1, and CYP4502E1 [5,63]. These results demonstrate that NOS are not optimal for the evaluation of the NO release from amidoximes. It is preferable to use the CYP450 pathway that shows good results with both amidoxime and oxime functions.

4.3. In Vivo and In Vitro Biological Responses to NO Release from Amidoximes/Oximes Oxidation Along with the discovery of the capacity of amidoximes and oximes to release NO in the presence of biological extracts and cells, many scientists started to test these products on biological tissues. Indeed, the in vivo generation of NO has gained a lot of attention among others due its capacity of vasodilatation and thus reducing platelet aggregation and thrombosis formation. The first major works that appeared on that topic were published by Rehse et al. in 1997 and 1998 [66,67]. Seven aryl azoamidoximes and their effects on thrombosis inhibition, blood pressure and inhibition of platelet aggregation were investigated [66]. Five of the seven amidoximes inhibited the formation of thrombus in mesenteric rat vessels and even two of these amidoximes inhibited the thrombus formation by more than 20% (Figure 10). The remaining two amidoximes bearing a methoxy or a fluoro group on the para position did not show any significant effect on the thrombus formation in both arterioles and venules. The inactive 4-methoxyphenylazo-methanamidoxime had also no significant action in lowering the blood pressure during 2, 4, 6, and 24 h. The highly active 4-chlorophenylazo-methanamidoxime decreased the blood pressure for 24 h with a maximum efficiency of 16% 10% at 6 h. It is noteworthy that both amidoximes were able to release NO in the presence ± of DEX-treated rat liver microsomes and NADPH, but only the second amidoxime was used by the cells in order to lower blood pressure and reduce thrombi formation. The last test conducted with these amidoximes was the platelet aggregation. All of the studied amidoximes exhibited low or poor activity after calculating their IC50 following the Born test. This means that these amidoximes are not able of being oxidized in these conditions. In another series of experiments, 17 compounds containing different aliphatic, aromatic, and bis-amidoximes were tested [67]. The results were in accordance with the previous study since the majority of the amidoximes showed a poor effect or even a lack of activity towards the inhibition of platelet aggregation which proves once more that the platelet rich plasma is not convenient for amidoximes oxidation. The most effective amidoxime was the aromatic one bearing a chlorine atom on the para position and an ethene group between the phenyl and the amidoxime function. The presence of this ethene group raised the efficiency for the platelet aggregation inhibition. Bis-amidoximes displayed a good activity for the inhibition of thrombus formation in arterioles and venules and the bis-amidoxime bearing an ethene group exhibited the highest percentage of thrombus inhibition. All other amidoximes also show some activity and it was noticed that adding a group on the para position may increase the thrombi formation inhibition, the key parameter being the lipophilicity rather than the electronic variations. The amidoximes exhibiting the highest activity in reducing the Molecules 2019, 24, x 12 of 18 majority of the amidoximes showed a poor effect or even a lack of activity towards the inhibition of platelet aggregation which proves once more that the platelet rich plasma is not convenient for amidoximes oxidation. The most effective amidoxime was the aromatic one bearing a chlorine atom on the para position and an ethene group between the phenyl and the amidoxime function. The presence of this ethene group raised the efficiency for the platelet aggregation inhibition. Bis- amidoximes displayed a good activity for the inhibition of thrombus formation in arterioles and venules and the bis-amidoxime bearing an ethene group exhibited the highest percentage of thrombusMolecules 2019 inhibition., 24, 2470 All other amidoximes also show some activity and it was noticed that adding12 of a 19 group on the para position may increase the thrombi formation inhibition, the key parameter being the lipophilicity rather than the electronic variations. The amidoximes exhibiting the highest activity thrombus formation were also tested for decreasing the blood pressure but their activity was weak in reducing the thrombus formation were also tested for decreasing the blood pressure but their (the highest effect was observed for the bis-amidoxime with a blood pressure lowering of only 5%) activity was weak (the highest effect was observed for the bis-amidoxime with a blood pressure (Figure 10). lowering of only 5%) (Figure 10). HO N HO N NH2 NH2 N N N N

Cl Most potent arylazoamidoximes in inhibition of thrombus formation Cl O NH2 NH2 H N OH H N OH NH2 NH2 2 N 2 N N N N N OH OH HO HO most potent compound among all Most potent aromatic and bis-amidoximes in inhibition of thrombus formation

O2N N N N N N N N N OH OH Most potent azide oximes in inhibition of thrombus formation Figure 10. Most potent amidoximes and oximes in the inhibition of thrombus formation according to Figure 10. Most potent amidoximes and oximes in the inhibition of thrombus formation according to the studies of Rehse et al. the studies of Rehse et al.

TheseThese studies werewere not not limited limited to amidoximesto amidoximes but alsobut toalso azide to azide oximes. oximes. These compoundsThese compounds showed showedbetter antiplatelet better antiplatelet effect than effect the than azide the amidoximes azide amidoximes and the and amidoximes the amidoximes since thesince majority the majority of the ofstudied the studied azide azide oximes oximes exhibited exhibited a capacity a capacity to inhibit to inhibit platelet platelet aggregation aggregation with with the the oxime oxime bearing bearing the the nitrophenyl function having an IC50 of 2 µmol/L in the Born test [68]. Similarly to amidoximes, nitrophenyl function having an IC50 of 2 µmol/L in the Born test [68]. Similarly to amidoximes, the theelectronic electronic variance variance and and the lipophilicitythe lipophilicity had nohad major no major rolein role changing in changing the effi theciency efficiency of the oximes,of the oximes,however however strong electronstrong electron withdrawing withdrawing groups groups like a nitro like functiona nitro function seem to seem increase to increase the oxime the activity.oxime activity.All of the All oximes of the oximes showed showed also 10–20% also 10%–20% efficiency efficiency in thrombus in thrombus formation formation inhibition inhibition and two and of themtwo ofexhibited them exhibited values highervalues thanhigher 20%. than Additionally, 20%. Addition azideally, oximes azide allowedoximes allowed a decrease a decrease of the blood of the pressure blood pressurethat may that reach may 10–15%. reach This 10%–15%. parameter This is notparamete connectedr is tonot the connected thrombus formationto the thrombus inhibition formation since the inhibitioncompound since exhibiting the compound the highest exhibiting antithrombotic the highes activityt antithrombotic did not have activity thehighest did not capacityhave the ofhighest blood capacitypressure of lowering. blood pressure Overall, lowering. the azide Overall, oximes showedthe azide to oximes be more showed effective to thanbe more the azideeffective amidoximes than the azideand other amidoximes studied and amidoximes other studied (Figure amidoximes 10). (Figure 10). InIn another another study study and and in in order order to to evaluate evaluate the the relaxation relaxation capacity capacity of of amidoximes, amidoximes, Jia Jia et et al. al. used used formamidoximeformamidoxime inin the the presence presence of a trachealof a tracheal ring previously ring previously contracted bycontracted carbachol, by a cholinomimeticcarbachol, a cholinomimeticdrug. They observed drug. They a relaxation observed a eff relaxationect on the effect tracheal on the ring tracheal after ring the incubationafter the incubation along with along an with an accumulation of the cyclic guanosine 3′,5′-monophosphate (cGMP) level after incubation with accumulation of the cyclic guanosine 30,50-monophosphate (cGMP) level after incubation with the thetracheal tracheal smooth smooth muscle muscle cells [cells69]. The[69]. relation The rela betweention between the production the production of cGMP of and cGMP the relaxationand the relaxationof the ring of was the provedring was by proved using by a cGMP using inhibitora cGMP inhibitor on both on the both tracheal the tracheal rings and rings the and smooth the smooth muscle musclecells. Thiscells. inhibitor This inhibitor prevented prevented the relaxation the relaxati ofon the of rings the rings and theand formation the formation of the of cGMP the cGMP in both in bothcultures. cultures. After After the the detection detection of of NO NO in in the the incubation incubation media media of of thethe trachealtracheal smooth muscle muscle cells cells with formamidoxime, the authors proposed that after the amidoxime oxidation, the released NO activates the formation of the cGMP which induces the relaxation of the tracheal ring. As previously, a NOS inhibitor was used with the cultured cells and the tracheal rings but it did not inhibit the production of cGMP or the relaxation of the rings. On the contrary, the cGMP production and the ring relaxation were both inhibited after the use of a CYP450 inhibitor, 7-ethoxyresorufin. Similarly, the cGMP production was inhibited after the use of Miconazole on the cell cultures. These results provided evidence that the pathway of the amidoxime oxidation in the tracheal smooth muscle cells Molecules 2019, 24, x 13 of 18 with formamidoxime, the authors proposed that after the amidoxime oxidation, the released NO activates the formation of the cGMP which induces the relaxation of the tracheal ring. As previously, a NOS inhibitor was used with the cultured cells and the tracheal rings but it did not inhibit the production of cGMP or the relaxation of the rings. On the contrary, the cGMP production and the ringMolecules relaxation2019, 24, 2470were both inhibited after the use of a CYP450 inhibitor, 7-ethoxyresorufin. Similarly,13 of 19 the cGMP production was inhibited after the use of Miconazole on the cell cultures. These results provided evidence that the pathway of the amidoxime oxidation in the tracheal smooth muscle cells and tracheal ring is through CYP450 and not NOS, and more specifically by CYP4501A1 being a strong and tracheal ring is through CYP450 and not NOS, and more specifically by CYP4501A1 being a substrate of the 7-ethoxyresorufin. strong substrate of the 7-ethoxyresorufin. This study using formamidoxime got a lot of attention and other researches were conducted to see This study using formamidoxime got a lot of attention and other researches were conducted to if this compound, along with other amidoximes and oximes, exhibited the same effects in the rat aorta. see if this compound, along with other amidoximes and oximes, exhibited the same effects in the rat Vetrovsky et al. tested a series of amidoximes and one oxime in the presence of endothelium-denuded aorta. Vetrovsky et al. tested a series of amidoximes and one oxime in the presence of endothelium- rat aorta (Figure 11) [70]. All of the compounds caused an endothelium-independent relaxation denuded rat aorta (Figure 11) [70]. All of the compounds caused an endothelium-independent higher than the NOHA with 4-chlorobenzamidoxime being the most active. It should also be noted relaxation higher than the NOHA with 4-chlorobenzamidoxime being the most active. It should also that formamidoxime (Table6, entry 1, in vitro studies) caused an important rat aorta relaxation be noted that formamidoxime (Table 6, entry 1, in vitro studies) caused an important rat aorta close to that of the 4-chlorobenzamidoxime. The authors demonstrate that the presence of relaxation close to that of the 4-chlorobenzamidoxime. The authors demonstrate that the presence of electron donating or withdrawing groups has a limited influence on the aorta relaxation since electron donating or withdrawing groups has a limited influence on the aorta relaxation since benzamidoxime, 4-methoxybenzamidoxime, and 4-n-(hexyloxy)benzamidoxime were slightly less benzamidoxime, 4-methoxybenzamidoxime, and 4-n-(hexyloxy)benzamidoxime were slightly less potent than 4-chlorobenzamidoxime and 4-nitrobenzamidoxime. Additionally, the lipophilicity increase potent than 4-chlorobenzamidoxime and 4-nitrobenzamidoxime. Additionally, the lipophilicity in 4-n-(hexyloxy)benzamidoxime compared to 4-methoxybenzamidoxime did not play a key role on increase in 4-n-(hexyloxy)benzamidoxime compared to 4-methoxybenzamidoxime did not play a key the relaxation effect. Finally, the use of an oxime instead of an amidoxime function caused a decrease role on the relaxation effect. Finally, the use of an oxime instead of an amidoxime function caused a in the relaxation capacity. decrease in the relaxation capacity.

R R = H, benzamidoxime Cl NH2 Cl, 4-chlorobenzamidoxime NH2 OCH3, 4-methoxybenzamidoxime N OC6H13, 4-n-(hexyloxy)benzamidoxime OH N NO , 4-nitrobenzamidoxime N OH 2 OH Formamidoxime Aromatic amidoximes 4-chloroacetophenone oxime Figure 11. Some of the studied amidoximes and oximes for their activity in rat aorta relaxation. Figure 11. Some of the studied amidoximes and oximes for their activity in rat aorta relaxation. Using the same tests but focusing on oximes like acetaldoxime, acetoxime and formaldoxime Using the same tests but focusing on oximes like acetaldoxime, acetoxime and formaldoxime (Table6, entries 2–4, in vitro studies), it was shown that all of these oximes are more potent to induce (Table 6, entries 2–4, in vitro studies), it was shown that all of these oximes are more potent to induce relaxation in rat aorta than hydroxyguanidine, formaldoxime being the most potent [71]. Similar to relaxation in rat aorta than hydroxyguanidine, formaldoxime being the most potent [71]. Similar to amidoximes, the lipophilicity increase from acetaldoxime to acetoxime does not significantly affect amidoximes, the lipophilicity increase from acetaldoxime to acetoxime does not significantly affect the induced relaxation. For the previously studied amidoximes and oximes, cGMP and NO were the induced relaxation. For the previously studied amidoximes and oximes, cGMP and NO were involved in the aorta relaxation since the addition of the guanylate cyclase inhibitor and NO-scavengers involved in the aorta relaxation since the addition of the guanylate cyclase inhibitor and NO- completely inhibited the relaxation. The use of NOS inhibitors and CYP450 inhibitors like proadifen scavengers completely inhibited the relaxation. The use of NOS inhibitors and CYP450 inhibitors like did not alter the relaxation effect, indicating that other oxidation pathways are involved with these proadifen did not alter the relaxation effect, indicating that other oxidation pathways are involved amidoximes and oximes. However, the use of the 7-ethoxyresorufin inhibited the relaxation of the with these amidoximes and oximes. However, the use of the 7-ethoxyresorufin inhibited the aorta rings in the presence of 4-chlorobenzamidoxime and oximes but the authors suggested that this relaxation of the aorta rings in the presence of 4-chlorobenzamidoxime and oximes but the authors is not due to an inhibition of the CYP4501A1 but to an inhibition of a different NADPH-dependent suggested that this is not due to an inhibition of the CYP4501A1 but to an inhibition of a different reductase pathway. In a following study [6], the aliphatic oximes and formamidoxime (Table6) were NADPH-dependent reductase pathway. In a following study [6], the aliphatic oximes and tested in vivo to evaluate the blood pressure decrease in conscious chronically cannulated rats in which formamidoxime (Table 6) were tested in vivo to evaluate the blood pressure decrease in conscious the endogenous NO synthesis was blocked. In the precedent in vitro studies, the three tested oximes chronically cannulated rats in which the endogenous NO synthesis was blocked. In the precedent in and the formamidoxime caused an aorta relaxation, contrariwise, in vivo only formamidoxime and vitro studies, the three tested oximes and the formamidoxime caused an aorta relaxation, formaldoxime were capable of lowering the blood pressure, with the amidoxime being the most active. contrariwise, in vivo only formamidoxime and formaldoxime were capable of lowering the blood This result was different from the in vitro experiments where the formaldoxime was the most potent. pressure, with the amidoxime being the most active. This result was different from the in vitro The inhibition of the guanylate cyclase in vivo caused the inhibition of the blood pressure reduction experiments where the formaldoxime was the most potent. The inhibition of the guanylate cyclase in when using formaldoxime, which indicates that NO is responsible for the whole effect while with vivo caused the inhibition of the blood pressure reduction when using formaldoxime, which indicates formamidoxime NO is responsible for one third of the effect, suggesting that with the amidoxime not that NO is responsible for the whole effect while with formamidoxime NO is responsible for one third the whole blood pressure decrease is caused by the NO release. Finally, hydrophilic substances were of the effect, suggesting that with the amidoxime not the whole blood pressure decrease is caused by found to be more active in vivo than in vitro. the NO release. Finally, hydrophilic substances were found to be more active in vivo than in vitro. More recently, other studies evaluated the potency of some oximes to induce a vasorelaxation in superior mesenteric arteries isolated from rats. It was demonstrated that E-cinnamaldehyde oxime was the most potent and able of causing a NOS and endothelium-independent vasorelaxation. The NO release and relaxation activity of this compound were only partially inhibited by 7-ethoxyresorufin, a CYP4501A1 specific inhibitor, but not by other CYP450 nonspecific inhibitor, which shows also Molecules 2019, 24, x 14 of 18 Molecules 2019, 24, 2470 14 of 19 Table 6. Comparison of some studied amidoximes and oximes for their aorta relaxation and pressure decrease abilities. that the oxime oxidation is catalysed by a NADPH-dependent reductase pathway in the superior mesentericMolecule arteries just likeIn Vitro the studies Rat Aorta in rat Relaxation aortic rings. In The Vivo relaxation Blood Pressure pathway Decrease is also caused by + 2+ the activation ofNH cGMP2 with a key role played by a type of K channel and the reduction of the Ca + influx [72]. TheN role of the K channels+++ was demonstrated in another study+++ published in 2014 after the incubationOH of an oxime with rat aortic rings in the presence of different channel blockers [73]. The relaxationFormamidoxime was observed when the enzyme and the aortic rings were incubated without the channel blockers. Furthermore, when administered to conscious rats, the oxime caused the reduction of blood N pressure. The aortaOH and superior mesenteric++ artery rings relaxations were similar× in the presence and in the absenceAcetaldoxime of the endothelium after the incubation with the oxime, indicating that NOS were not responsible of the oxidation. The relaxation, as for the previously studied compounds, is achieved by the release of NON and the activation of the++ cGMP pathway alongside the activation× of the K+ channels. Molecules 2019, 24, xOH 14 of 18 Molecules 2019,Acetoxime 24, x 14 of 18 Molecules 2019, 24, x 14 of 18 Table 6. ComparisonOH of some studied amidoximes and oximes for their aorta relaxation and pressure MoleculesTable 2019 6., 24Com, x parison of some studied amidoximes and oximes for their aorta relaxation and pressure14 of 18 decreaseTable 6. abilities.ComN parison of some studied amidoximes and oximes for their aorta relaxation and pressure decreaseTable 6. Comabilities.parison of some studied amidoximes and oximes for their aorta relaxation and pressure decreaseTable 6. Comabilities.parison of some studied++++ amidoximes and oximes for their aorta++ relaxation and pressure decreaseMoleculeNN abilities. In Vitro Rat Aorta Relaxation In Vivo Blood Pressure Decrease decreaseHOMolecule abilities.OH In Vitro Rat Aorta Relaxation In Vivo Blood Pressure Decrease MoleculeNH In Vitro Rat Aorta Relaxation In Vivo Blood Pressure Decrease Formaldoxime2 MoleculeNH2 In Vitro Rat Aorta Relaxation In Vivo Blood Pressure Decrease MoleculeNH In Vitro Rat Aorta Relaxation In Vivo Blood Pressure Decrease N 2 ++++ highly active;++++++ +++ active; ++ weakly active; × inactive. ++++++ N NHOH2 OH +++ +++ FormamidoximeN +++ +++ More recently,N OH other studies evaluated the potency of some oximes to induce a vasorelaxation FormamidoximeOH +++ +++ in superiorFormamidoxime mesenteric arteries isolated from rats. It was demonstrated that E-cinnamaldehyde oxime FormamidoximeN ++ × was the most NpotentOH and able of causing++++ a NOS and endothelium-independent× vasorelaxation. The N OH × NO releaseAcetaldoxime andOH relaxation activity of++ this compound were only partially× inhibited by 7- AcetaldoximeN OH ++ × ethoxyresorufin,Acetaldoxime a CYP4501A1 specific inhibitor, but not by other CYP450 nonspecific inhibitor, which shows also thatAcetaldoximeN the oxime oxidation is catalyse++ d by a NADPH-dependent ×reductase pathway in the N OH ++ × superior mesentericN OH arteries just like the studies in rat aortic rings. The relaxation pathway is also AcetoximeOH ++++ × AcetoximeN × caused by the activationOHOH of cGMP with ++a key role played by a type of K+ channel× and the reduction AcetoximeOH 2+ AcetoximeOHN + of the Ca influxN [72]. The role of the K channels was demonstrated in another study published in OH 2014 after the NNincubationN of an oxime with++++ rat aortic rings in the presence of+ different+ channel blockers HO NNN OH ++++ ++ [73]. The relaxationHO NN wasOH observed when++++ the enzyme and the aortic rings were++ incubated without the channel blockers.HOFormaldoximeNN Furthermore,OH when administered++++++++ to conscious rats, the oxime ++++ caused the reduction HOFormaldoximeOH of blood pressure.Formaldoxime The aorta and superior mesenteric artery rings relaxations were similar in the Formaldoxime presence and in the absence of the endothelium after the incubation with the oxime, indicating that NOS were not responsible++++ of thehighly oxidation. active; +++ Theactive; relaxation,++ weakly as active; for theinactive. previously studied compounds, ++++ highly active; +++ active; ++ weakly× active; × inactive. is achieved by the release of NO++++ and highly the active;activation +++ active; of the ++cGMP weakly pathway active; × alongside inactive. the activation of + ++++ highly active; +++ active; ++ weakly active; × inactive. the KIn channels. addition, More amidoximes recently, can++++ other also highly be studies active; used for evaluated+++ their active; capacity ++ the weakly potenc of loweringactive;y of × someinactive. the intraocular oximes to pressure induce a (IOP)In in addition, rabbits dueMore amidoximes to the recently, NO release can other also followed be studies used by for evaluated the thei formationr capacity the ofpotenc of cGMP loweringy [of74 , some75 the]. In intraocular oximes 2006, Oresmaa to pressure induce et al. a vasorelaxationMore recently, in superior other studies mesenteric evaluated arteries the isolated potenc fromy of somerats. It oximes was demonstrated to induce a tested(IOP) in various rabbitsvasorelaxation imidazole dueMore to recently,the amidoximes NOin superior release other for studiesfollowed mesenteric their IOP-loweringevaluated by arteriesthe formation the isolated abilities. potenc of cGMP fromy Two of somerats. [74,75]. of them It oximes was In (Figure 2006, demonstrated to Oresmaa12 induce) were a thatvasorelaxation E-cinnamaldehyde in superior oxime mesenteric was the arteries most potent isolated and from able rats. of It causing was demonstrated a NOS and ableet al. to tested producevasorelaxationthat various NOE-cinnamaldehyde andimidazole increase in superioramidoximes the oximecGMP mesenteric formationwasfor their the arteries IOP-lowering most when potent incubatedisolated andabilities. from with able rats. porcine Two of It causing of was iris-ciliarythem demonstrated a(Figure NOS bodies a12)nd endothelium-independentthat E-cinnamaldehyde oxime vasorela wasxation. the most The NO potent release and ableand ofrelaxation causing aactivity NOS andof butwere only able the toendothelium-independentthat produce methyl E-cinnamaldehyde formNO and was increase able oxime to vasorela the reduce cGMPwasxation. the the formation IOP most The when potentNO when administered release incubated and ableand intravitreally ofwithrelaxation causing porcine a activity iris-ciliary in NOS rabbits. a ndof thisendothelium-independent compound were only vasorela partiallyxation. inhibited The NO byrelease 7-ethoxyresorufin, and relaxation a CYP4501Aactivity of1 Thebodies esterification but endothelium-independentthisonly compoundthe of themethyl active formwere amidoximes wasonly vasorela able pa caused tortially xation.redu the ceinhibited lossThethe ofNOIOP their whenbyrelease biological 7- administeredethoxyresorufin, and activity.relaxation intravitreally a CYP4501Aactivity inof1 specificthis compound inhibitor, butwere not only by other partially CYP450 inhibited nonspecific by inhibitor,7-ethoxyresorufin, which shows a CYP4501A also that1 rabbits. Thethisspecific esterification compound inhibitor, of the butwere active not only by amidoxim otherpartially CYP450es causedinhibited nonspecific the lossby ofinhibitor,7- theirethoxyresorufin, biological which shows activity. a CYP4501A also that1 thespecific oxime inhibitor, oxidation but isnot catalyse by otherd byCYP450 a NADPH-dependent nonspecific inhibitor, reductase which pashowsthway also in that the specificthe oxime inhibitor, oxidation but isnot catalyse by otherd byCYP450 a NADPH-dependent nonspecific inhibitor, reductase which pashowsthway also in that the superiorthe oxime mesenteric oxidation arteries is catalyse justd likeby a the NADPH-dependent studies in rat aortic reductase rings. pa Thethway relaxation in the thesuperior oxime mesenteric oxidation arteries is catalyse justd bylike a the NADPH-dependent studies in rat aortic reductase rings. pa Thethway relaxation in the pathwaysuperior is mesenteric also caused arteries by the justactivation like the of cGMP studies with in rata key aortic role rings. played The by relaxationa type of superiorpathway+ is mesenteric also caused arteries by the just activation like the2+ of cGMP studies with in rata key aortic role rings. played + The by relaxationa type of Kpathway channel is andalso thecaused reduction by the ofactivation the Ca of influx cGMP [72 with]. The a key role role of theplayed K cha bynnels a type was of pathwayK+ channel is alsoand thecaused reduction by the activationof the Ca2+ of influx cGMP [72 with]. The a key role role of theplayed K+ cha bynnels a type was of demonstratedK+ channel and in theanother reduction study of published the Ca2+ influxin 2014 [72 after]. The the roleincu bationof the ofK+ ancha oximennels withwas Kdemonstrated+ channel and in theanother reduction study of published the Ca2+ influxin 2014 [72 after]. The the roleincu bationof the ofK+ ancha oximennels withwas rademonstratedt aortic rings in in another the presence study published of different in channel2014 after blockers the incu [73].bation The of relaxaan oximetion with was demonstratedrat aortic rings in in another the presence study published of different in channel2014 after blockers the incu [73].bation The of relaxaan oximetion with was observedrat aorticFigure when rings 12.12. in the Imidazole the enzyme presence amidoximes and of the different aorticable toto increaseringsincrease channel were cGMPcGMP blockers incubated formation.formation. [73]. without The relaxa thetion channel was raobservedt aortic when rings in the the enzyme presence and of the different aortic rings channel were blockers incubated [73]. without The relaxa thetion channel was blockers.observed Furthermore,when the enzyme when and administered the aortic rings to conscious were incubated rats, the without oxime the caused channel the All of theseobservedblockers. studies whenFurthermore, demonstrate the enzyme thatwhen when and administered theamidoximes aortic rings to or consciousoximes were are incubated incubatedrats, the without oximewith cultured the caused channel cells the All of thesereductionblockers. studies Furthermore,of demonstrate blood pressure. when that when administered The amid aortaoximes to and consciousor suoximesperior rats,are mesenteric incubated the oxime with artery caused cultured rings the such as trachealblockers.reduction smooth Furthermore,of muscle blood cells pressure. [when69] or with administered The biological aorta to tissues and conscious su suchperior as rats, aortic mesenteric the/tracheal oxime ringsartery caused [ 69 rings, 70 the], cells such asrelaxationsreduction tracheal smooth ofwere blood musclesimilar pressure. cellsin the [69] presence The or with aorta biologicaland andin the sutissues absenceperior such mesentericof asthe aortic/tracheal endothelium artery rings ringsafter reductionrelaxations ofwere blood similar pressure. in the presence The aorta and andin the su absenceperior mesentericof the endothelium artery ringsafter therelaxations incubation were with similar the in oxime, the presence indicating and thatin the NOS absence were of not the responsibleendothelium of afte ther therelaxations incubation were with similar the in oxime, the presence indicating and thatin the NOS absence were of not the responsibleendothelium of afte ther oxtheidation. incubation The relaxation, with the as oxime, for the indicating previously that studied NOS compounds, were not responsibleis achieved by of the theoxidation. incubation The relaxation, with the as oxime, for the indicating previously that studied NOS compounds, were not responsibleis achieved ofby the+ releaseoxidation. of NO The and relaxation, the activation as for ofthe the previously cGMP pathway studied a longsidecompounds, the activationis achieved of bythe the K releaseoxidation. of NOThe and relaxation, the activation as for ofthe the previously cGMP pathway studied a longsidecompounds, the activationis achieved of bythe the K+ channels.release of NO and the activation of the cGMP pathway alongside the activation of the K+ releasechannels. of NO and the activation of the cGMP pathway alongside the activation of the K+ channels.In addition, amidoximes can also be used for their capacity of lowering the channels.In addition, amidoximes can also be used for their capacity of lowering the intraocularIn addition, pressure amidoximes (IOP) in rabbits can due also to be the used NO forrelease thei followedr capacity by ofthe loweringformation the of intraocularIn addition, pressure amidoximes (IOP) in rabbits can alsodue to be the used NO forrelease thei followedr capacity by ofthe lowering formation the of cGMPintraocular [74,75]. pressure In 2006, (IOP) Oresmaa in rabbits et due al. tested to the variousNO release imidazole followed amidoximes by the formation for their of intraocularcGMP [74,75]. pressure In 2006, (IOP) Oresmaa in rabbits et due al. tested to the variousNO release imidazole followed amidoximes by the formation for their of IOP-loweringcGMP [74,75]. abilities. In 2006, Two Oresmaa of them et al.(Figure tested 12) various were able imidazole to produce amidoximes NO and forincrease their cGMPIOP-lowering [74,75]. abilities. In 2006, Two Oresmaa of them et al.(Figure tested 12) various were able imidazole to produce amidoximes NO and forincrease their theIOP-lowering cGMP formation abilities. whenTwo of incubated them (Figure with 12) porcine were able iris-cilia to producery bodies NO but and only increase the IOP-loweringthe cGMP formation abilities. whenTwo of incubated them (Figure with 12) porcine were able iris-cilia to producery bodies NO but and onlyincrease the methylthe cGMP form formation was able whento redu incubatedce the IOP with when porcine administered iris-cilia ryintra bodiesvitreally but in only rabbits. the methylthe cGMP formFigure formation wa 12.s Imidazoleable whento redu amidoximes incubatedce the IOP able with whento increase porcine administered cGMP iris-cilia formation. ryintra bodiesvitreally but in only rabbits. the Themethyl esterifica formFigure tionwa 12.s of Imidazoleable the toactive redu amidoximes amidoximce the IOP ablees causedtowhen increase administeredthe cGMP loss of formation. their intra biological vitreally activity. in rabbits. methylThe esterifica formFigure tionwa 12.s of Imidazoleable the toactive redu amidoximes amidoximce the IOP ablees caused whento increase administeredthe cGMPloss of formation. their intra biologicalvitreally activity. in rabbits. All of Thethese esterifica studiesFigure tiondemonstrate 12. of Imidazole the active that amidoximes amidoxim when amid ablees oximes causedto increase orthe oximescGMP loss of formation. aretheir incubated biological with activity. cultured All of Thethese esterifica studies tiondemonstrate of the active that amidoxim when amides oximescaused orthe oximes loss of aretheir incubated biological with activity. cultured cells Allsuch of as these tracheal studies smooth demonstrate muscle cells that [69]when or amidwith oximesbiological or oximestissues aresuch incubated as aortic/tracheal with cultured rings cells Allsuch of as these tracheal studies smooth demonstrate muscle cells that [69]when or amidwith oximesbiological or oximestissues aresuch incubated as aortic/tracheal with cultured rings cells such as tracheal smooth muscle cells [69] or with biological tissues such as aortic/tracheal rings cells such as tracheal smooth muscle cells [69] or with biological tissues such as aortic/tracheal rings Molecules 2019, 24, 2470 15 of 19 the generation of NO followed by the relaxation of the tissues is observed. This relaxation was proved to be caused by an increase in the cGMP accumulation after the activation of the guanylate cyclase by the released NO. Moreover, even in biological tissues, the NOS pathway does not seem to play a role in the oxidation of these products [69–71]. However, in some biological tissues like aortic rings and superior mesenteric arteries, CYP450 did not seem to play a role in the oxidation but it was suggested to be another NADPH-dependent reductase pathway [70–72]. Independently from the enzyme involved in the oxidation of amidoximes and oximes, it is now well established that the related NO release causes an activation of the guanylate cyclase with an accumulation of cGMP. This is followed by an activation of the BKCa channels which causes an efflux of the potassium ions and thus a decrease in the calcium channels activity [72,73]. This pathway causes a relaxation in the targeted tissue along the detected effects such as blood pressure decrease.

5. Conclusions Amidoximes and oximes are compounds that are easy to synthesize and that present many benefits especially in biological pathways. In this review, we focused on their NO donor abilities. Many oximes and amidoximes can be oxidized by the CYP450 route rather than the NOS pathway which is of high interest when the patient’s NOS is not functional. Additionally, these compounds showed in vitro and in vivo abilities to cause the relaxation of aortas, to inhibit platelet aggregation and to decrease the hypertension. For all these reasons, amidoximes and oximes are of high potential for future use against many cardiovascular diseases.

Author Contributions: Writing—original draft preparation, T.S.; writing—review and editing, A.A; writing—review and editing, R.S. Funding: This research received no external funding. Conflicts of Interest: The authors declare no conflict of interest.

References

1. Bolotin, D.S.; Bokach, N.A.; Kukushkin, V.Y. Coordination Chemistry and Metal-Involving Reactions of Amidoximes: Relevance to the Chemistry of Oximes and Oxime Ligands. Coord. Chem. Rev. 2016, 313, 62–93. [CrossRef] 2. Tamada, M.; Seko, N.; Yoshii, F. Application of Radiation-Graft Material for Metal Adsorbent and Crosslinked Natural Polymer for Healthcare Product. Radiat. Phys. Chem. 2004, 71, 221–225. [CrossRef] 3. Seko, N.; Tamada, M.; Yoshii, F. Current Status of Adsorbent for Metal Ions with Radiation Grafting and Crosslinking Techniques. Nucl. Instrum. Methods Phys. Res. Sect. B Beam Interact. Mater. At. 2005, 236, 21–29. [CrossRef] 4. Vadon-Le Goff, S.; Boucher, J.-L.; Mansuy, D. Oxidation of Arylamidoximes by Various Chemical and Biomimetic Systems: Comparison with Their Oxidations by Hemeproteins. C. R. Acad. Sci. Ser. IIC Chem. 2000, 3, 785–792. [CrossRef] 5. Jousserandot, A.; Boucher, J.-L.; Henry, Y.; Niklaus, B.; Clement, B.; Mansuy, D. Microsomal Cytochrome P450 Dependent Oxidation of N-Hydroxyguanidines, Amidoximes, and Ketoximes: Mechanism of the Oxidative Cleavage of Their C=N(OH) Bond with Formation of Nitrogen Oxides. Biochemistry 1998, 37, 17179–17191. [CrossRef][PubMed] 6. Jaroš, F.; Straka, T.; Dobešová, Z.; Pintérová, M.; Chalupský, K.; Kuneš, J.; Entlicher, G.; Zicha, J. Vasorelaxant Activity of Some Oxime Derivatives. Eur. J. Pharmacol. 2007, 575, 122–126. [CrossRef] [PubMed] 7. Fylaktakidou, K.C.; Hadjipavlou-Litina, D.J.; Litinas, K.E.; Varella, E.A.; Nicolaides, D.N. Recent Developments in the Chemistry and in the Biological Applications of Amidoximes. Curr. Pharm. Des. 2008, 14, 1001–1047. [CrossRef][PubMed] 8. Mansuy,D.; Boucher, J.-L.; Clement, B. On the Mechanism of Nitric Oxide Formation upon Oxidative Cleavage of C=N(OH) Bonds by NO-Synthases and Cytochromes P450. Biochimie 1995, 77, 661–667. [CrossRef] 9. Logan, R.T.; Redpath, J.; Roy, R.G. Indene and Naphthalene Derivatives. E.P. 0,199,393, 29 October 1986. Molecules 2019, 24, 2470 16 of 19

10. Huang, C.-T.; Pelosi, S.S., Jr.; Bayless, A.V. N-Hydroxy-5-Phenyl-2-Furancarboximidamides Useful As Cardiotonic Agents. U.S. Patent 4,882,354, 21 November 1989. 11. Shahid, M.; Martorana, M.G.; Cottney, J.E.; Marshall, R.J. Pharmacological and Biochemical Effects of the Cardiotonic Agent Org10325 in Isolated Cardiac and Vascular Tissue Preparations. Br. J. Pharmacol. 1990, 100, 735–742. [CrossRef] 12. Desmukh, S.S.; Huddar, S.N.; Bhalerao, D.S.; Akamanchi, K.G. Oxidation of Amidoximes with IBX and IBX/TEAB. Arkivoc 2010, 2010, 118–126. 13. Hall, J.E.; Kerrigan, J.E.; Ramachandran, K.; Bender, B.C.; Stanko, J.P.; Jones, S.K.; Patrick, D.A.; Tidwell, R.R. Anti-Pneumocystis Activities of Aromatic Diamidoxime Prodrugs. Antimicrob. Agents Chemother. 1998, 42, 666–674. [CrossRef][PubMed] 14. Clement, B.; Bürenheide, A.; Rieckert, W.; Schwarz, J. Diacetyldiamidoximeester of Pentamidine, a Prodrug for Treatment of Protozoal Diseases: Synthesis, in Vitro and in Vivo Biotransformation. ChemMedChem 2006, 1, 1260–1267. [CrossRef][PubMed] 15. Tavakol, H.; Arshadi, S. Theoretical Investigation of Tautomerism in N-Hydroxy Amidines. J. Mol. Model. 2009, 15, 807–816. [CrossRef][PubMed] 16. Novikov, A.S.; Bolotin, D.S. Tautomerism of Amidoximes and Other Oxime Species. J. Phys. Org. Chem. 2017, 31, e3772. [CrossRef] 17. Bell, C.L.; Nambury, C.N.V.; Bauer, L. The Structure of Amidoximes. J. Org. Chem. 1964, 29, 2873–2877. [CrossRef] 18. Gł˛ebocka,A.; Raczy´nska,E.D.; Chylewska, A.; Makowski, M. Experimental (FT-IR) and Theoretical (DFT) Studies on Prototropy and H-Bond Formation for Pyrazine-2-Amidoxime: FT-IR and DFT Studies on Pyrazine-2-Amidoxime. J. Phys. Org. Chem. 2016, 29, 326–335. [CrossRef] 19. Blatt, A.H. The Tautomerism of Oximes. J. Org. Chem. 1938, 3, 91–98. [CrossRef] 20. Bohle, D.S.; Chua, Z.; Perepichka, I.; Rosadiuk, K. E/Z Oxime Isomerism in PhC(NOH)CN. Chem. Eur. J. 2013, 19, 4223–4229. [CrossRef] 21. Vijfhuizen, P.C.; Terlouw, J.K. On the Loss of CH3. from O-Methylbenzaldoxime. Evidence for an Ortho Assisted Oxime nitrone Isomerization. Org. Mass Spectrom. 1977, 12, 63–64. [CrossRef] → 22. Long, J.A.; Harris, N.J.; Lammertsma, K. Formaldehyde Oxime Nitrosomethane Tautomerism. J. Org. Chem. 2001, 66, 6762–6767. [CrossRef] 23. Roca-López, D.; Darù, A.; Tejero, T.; Merino, P. Revisiting Oxime–Nitrone Tautomerism. Evidence of Nitrone Tautomer Participation in Oxime Nucleophilic Addition Reactions. RSC Adv. 2016, 6, 22161–22173. [CrossRef] 24. Dignam, K.J.; Hegarty, A.F. Reactivity of 1.3-Dipoles in Aqueous Solution. Part 4.l Kinetics and Mechanism of Isomerisation of Amidoximes in Aqueous Solution. J. Chem. Soc. Perkin Trans. 2 1979, 1437–1443. [CrossRef] 25. Belmar, J.; Quezada, J.; Jiménez, C.A.; Díaz-Gallifa, P.; Pasán, J.; Ruiz-Pérez, C. Synthesis, Crystal Structures and Tautomerism in Novel Oximes Based on Hydroxyalkylpyrazolones. N. J. Chem. 2013, 37, 2002–2010. [CrossRef] 26. Noguchi, M.; Okada, H.; Tanaka, M.; Matsumoto, S.; Kakehi, A.; Yamamoto, H. Mechanistic Considerations on the Oxime–Nitrone Isomerization and Intramolecular Cycloaddition Reaction of 3-(Alk-2-Enylamino) Propionaldehyde Oximes. Bull. Chem. Soc. Jpn. 2001, 74, 917–925. [CrossRef] 27. Heaney, F.; Bourke, S.; Cunningham, D.; McArdle, P. Steric Control of Reactivity: Formation of Oximes, Benzodiazepinone N-Oxides and Isoxazoloquinolinones. J. Chem. Soc. Perkin Trans. 2 1998, 547–559. [CrossRef] 28. Gotoh, M.; Mizui, T.; Sun, B.; Hirayama, K.; Noguchi, M. Intramolecular 1,3-Dipolar Cycloaddition at the Periphery of Heterocyclic Systems. Part 1. Facile Oxime–Nitrone Isomerisation at the Periphery of Pyran and 1-Benzopyran. J. Chem. Soc. Perkin 1 1995, 1857–1862. [CrossRef] 29. Lossen, W.; Schifferdecker, P. Isuretine, a Base Isomeric with Urea. Ann. Chem. Pharm. 1973, 26, 295–320. 30. Nicolaides, D.N.; Varella, E.A. The Chemistry of Amidoximes. In The Chemistry of Acid Derivatives; Patai, S., Ed.; The Chemistry of Functional Groups; Wiley: Chichester, UK; New York, NY, USA, 1992; Volume 2, pp. 875–927. 31. Tiemann, T. Effect of Hydroxylamine on Nitriles. Chem. Ber. 1884, 17, 126–129. [CrossRef] 32. Kosary, J.; Kasztreiner, E.; Andrasi, F. Synthesis of Pyridylthiazoles as Antisecretory Agents. Pharmazie 1989, 44, 191–193. Molecules 2019, 24, 2470 17 of 19

33. Warburton, W.K. The Reaction of Benzoyldicyandiamide [PhCO NH C(NH2): N CN] with Hydroxylamine · · · Hydrochloride to Give Oxadiazoles. J. Chem. Soc. C Org. 1966, 1522–1524. [CrossRef] 34. Bjorklund, M.D.; Coburn, M.D. 3,3-Dinitrobutyl-1.2.4-Oxadiazoles (1). J. Heterocycl. Chem. 1980, 17, 819–821. [CrossRef] 35. Cashman, J.R.; Kalisiak, J. Blood Brain Barrier-Penetrating Oximes for Cholistenerases Reactivation. U.S. Patent 9,751,831, 5 September 2017. 36. Yahya, A.M. Synthesis of Some Heterocyclic Compounds from Amidoxime and Imidate. Rafidain J. Sci. 2008, 19, 59–68. 37. Ovdiichuk, O.; Hordiyenko, O.; Medviediev, V.; Shishkin, O.; Arrault, A. Efficient Synthesis of Nicotinic Acid Based Pseudopeptides Bearing an Amidoxime Function. Synthesis 2015, 47, 2285–2293. 38. Sahyoun, T.; Gaucher, C.; Zhou, Y.; Ouaini, N.; Schneider, R.; Arrault, A. Synthesis of Novel Mono and Bis Nitric Oxide Donors with High Cytocompatibility and Release Activity. Bioorg. Med. Chem. Lett. 2018, 28, 3329–3332. [CrossRef][PubMed] 39. Lee, W.M. Copper cmp Polishing Pad Cleaning Composition Comprising of Amidoxime Compounds. U.S. Patent 0,137,191, 28 May 2009. 40. Ranjbar-Karimi, R.; Davodian, T.; Mehrabi, H. Survey Reactivity of Some Substituted Quinazolinones with Pentafluoro(Chloro)Pyridine. J. Heterocycl. Chem. 2018, 55, 475–480. [CrossRef] 41. Katritzky, A.R.; Khashab, N.M.; Kirichenko, N.; Singh, A. Microwave-Assisted Preparations of Amidrazones and Amidoximes. J. Org. Chem. 2006, 71, 9051–9056. [CrossRef][PubMed] 42. Ovdiichuk, O.V.; Hordiyenko, O.V.; Arrault, A. Synthesis and Conformational Study of Novel Pyrazine-Based Pseudopeptides Bearing Amidoxime, Amidoxime Ester and 1,2,4-Oxadiazole Units. Tetrahedron 2016, 72, 3427–3435. [CrossRef] 43. Ovdiichuk, O.; Hordiyenko, O.; Fotou, E.; Gaucher, C.; Arrault, A.; Averlant-Petit, M.-C. Conformational Studies of New Pseudotripeptide with Pyrazine Amidoxime Motif and Simplified Analogs Using IR, NMR Spectroscopy, and Molecular Dynamic Simulations. Struct. Chem. 2016, 28, 813–822. [CrossRef] 44. Lossen, W. Structural Formulae of Hydroxylamine and Its Derivatives. Justus Liebigs Annalen Chemie 1889, 252, 170–240. [CrossRef] 45. Wieland, H.; Bauer, H. Benzenylnitrosolic Acid. Berichte Deutschen Chemischen Gesellschaft 1906, 39, 1480–1488. [CrossRef] 46. Tyrkov, A.G.; Usova, A.N. Reduction of Substituted 5-(Nitromethyl)-3-Phenyl-1,2,4-Oxadiazoles. Russ. J. Org. Chem. 2004, 40, 286–287. [CrossRef] 47. Bakó, E.M.; Horváth, K.; Pálosi, E.; Korbonits, D. Formation of α-(Acylamino) Butyramide Oximes from 5-Substituted 3-(1-Aminopropyl)-1,2,4-Oxadiazoles: An Astonishing Hydrolytic Transformation. Chemische Bericthe 1988, 121, 723–726. [CrossRef] 48. Fujii, T.; Saito, T.; Kumazawa, Y. Purines. XL.: Preparation of 9-(ω-Carboxyalkyl)-3-Methyladenines. Chem. Pharm. Bull. (Tokyo) 1990, 38, 1392–1395. [CrossRef] 49. Kuruba, B.K.; Vasanthkumar, S. An Efficient Protocol for the Synthesis of Six-Membered N, O-Heterocycles via a 1,3-Dipolar (3+3) Cycloaddition between Nitrile Oxide and α-Diazo Esters. Tetrahedron 2017, 73, 3860–3865. [CrossRef] 50. Kool, E.T.; Crisalli, P.; Chan, K.M. Fast Alpha Nucleophiles: Structures That Undergo Rapid Hydrazone/Oxime Formation at Neutral pH. Org. Lett. 2014, 16, 1454–1457. [CrossRef][PubMed] 51. Hajipour, A.R.; Mallakpour, S.E.; Imanzadeh, G. A Rapid and Convenient Synthesis of Oximes in Dry Media under Microwave Irradiation. J. Chem. Res. 1999, 228–229. [CrossRef] 52. Sharghi, H.; Hosseini, M. Solvent-Free and One-Step Beckmann Rearrangement of Ketones and Aldehydes by Zinc Oxide. Synthesis 2002, 1057–1060. [CrossRef] 53. Li, J.-T.; Li, X.-L.; Li, T.-S. Synthesis of Oximes under Ultrasound Irradiation. Ultrason. Sonochem. 2006, 13, 200–202. [CrossRef][PubMed] 54. Patil, V.V.; Gayakwad, E.M.; Shankarling, G.S. m-CPBA Mediated Metal Free, Rapid Oxidation of Aliphatic Amines to Oximes. J. Org. Chem. 2016, 81, 781–786. [CrossRef] 55. Anggard, E. Nitric Oxide: Mediator, Murderer, and Medicine. Lancet 1994, 343, 1199–1206. [CrossRef] 56. Knowles, R.G.; Moncada, S. Nitric Oxide as a Signal in Blood Vessels. Trends Biochem. Sci. 1992, 17, 399–402. [CrossRef] Molecules 2019, 24, 2470 18 of 19

57. Koikov, L.N.; Alexeeva, N.V.; Lisitza, E.A.; Krichevsky, E.S.; Grigoryev, N.B.; Danilov, A.V.; Severina, I.S.; Pyatakova, N.V.; Granik, V.G. Oximes, Amidoximes and Hydroxamic Acids as Nitric Oxide Donors. Mendeleev Commun. 1998, 8, 165–168. [CrossRef] 58. Öcal, N.; Erden, I. Oxidative Cleavage of the C=N Bond during Singlet Oxygenations of Amidoximates. Tetrahedron Lett. 2001, 42, 4765–4767. [CrossRef] 59. Boucher, J.-L.; Genet, A.; Vadon, S.; Delaforge, M.; Henry, Y.; Mansuy, D. Cytochrome P450 Catalyzes the Oxidation of Nω-Hydroxy-L-Arginine by NADPH and O2 to Nitric Oxide and Citrulline. Biochem. Biophys. Res. Commun. 1992, 187, 880–886. [CrossRef] 60. Andronik-Lion, V.; Boucher, J.-L.; Delaforge, M.; Henry, Y.; Mansuy, D. Formation of Nitric Oxide by Cytochrome P450-Catalyzed Oxidation of Aromatic Amidoximes. Biochem. Biophys. Res. Commun. 1992, 185, 452–458. [CrossRef] 61. Mäntylä, A.; Rautio, J.; Nevalainen, T.; Vepsälainen, J.; Juvonen, R.; Kendrick, H.; Garnier, T.; Croft, S.L.; Järvinen, T. Synthesis and Antileishmanial Activity of Novel Buparvaquone Oxime Derivatives. Bioorg. Med. Chem. 2004, 12, 3497–3502. [CrossRef][PubMed] 62. Mäntylä, A.; Rautio, J.; Nevalainen, T.; Keski-Rahkonen, P.; Vepsälainen, J.; Järvinen, T. Design, Synthesis and in Vitro Evaluation of Novel Water-Soluble Prodrugs of Buparvaquone. Eur. J. Pharm. Sci. 2004, 23, 151–158. [CrossRef][PubMed] 63. Caro, A.A.; Cederbaum, A.I.; Stoyanovsky, D.A. Oxidation of the Ketoxime Acetoxime to Nitric Oxide by Oxygen Radical-Generating Systems. Nitric Oxide 2001, 5, 413–424. [CrossRef] 64. Moali, C.; Brollo, M.; Custot, J.; Sari, M.-A.; Boucher, J.-L.; Stuehr, D.J.; Mansuy, D. Recognition of α-Amino Acids Bearing Various C=NOH Functions by Nitric Oxide Synthase and Arginase Involves Very Different Structural Determinants. Biochemistry 2000, 39, 8208–8218. [CrossRef] 65. Renodon-Cornière, A.; Dijols, S.; Perollier, C.; Lefevre-Groboillot, D.; Boucher, J.-L.; Attias, R.; Sari, M.-A.; Stuehr, D.; Mansuy, D. N-Aryl N’-Hydroxyguanidines, a New Class of NO-Donors after Selective Oxidation by Nitric Oxide Synthases: Structure activity Relationship. J. Med. Chem. 2002, 45, 944–954. [CrossRef] − 66. Rehse, K.; Bade, S.; Harsdorf, A.; Clement, B. New NO-Donors with Antithrombotic and Vasodilating Activities, Part 17. Arylazoamidoximes and 3-Arylazo-1,2,4-Oxadiazol-5-Ones. Arch. Pharm. (Weinh.) 1997, 330, 392–398. [CrossRef] 67. Rehse, K.; Brehme, F. New NO Donors with Antithrombotic and Vasodilating Activities, Part 26 Amidoximes and Their Prodrugs. Arch. Pharm. (Weinh.) 1998, 331, 375–379. [CrossRef] 68. Rehse, K.; Brehme, F. New NO Donors with Antithrombotic and Vasodilating Activities, Part 27 Azide Oximes and 1-Hydroxytetrazoles. Arch. Pharm. (Weinh.) 2000, 333, 157–161. [CrossRef] 69. Jia, Y.; Zacour, M.; Tolloczko, B.; Martin, J.G. Nitric Oxide Synthesis by Tracheal Smooth Muscle Cells by a Nitric Oxide Synthase-Independent Pathway. Am. J. Physiol. 1998, 275, L895–L901. [CrossRef][PubMed] 70. Vetrovsky, P.; Boucher, J.-L.; Schott, C.; Beranova, P.; Chalupsky, K.; Callizot, N.; Muller, B.; Entlicher, G.; Mansuy, D.; Stoclet, J.-C. Involvement of NO in the Endothelium-Independent Relaxing Effects of Nω-Hydroxy-L-Arginine and Other Compounds Bearing a C=NOH Function in the Rat Aorta. J. Pharmacol. Exp. Ther. 2002, 303, 823–830. [CrossRef][PubMed] 71. Chalupsky, K.; Lobysheva, I.; Nepveu, F.; Gadea, I.; Beranova, P.; Entlicher, G.; Stoclet, J.-C.; Muller, B. Relaxant Effect of Oxime Derivatives in Isolated Rat Aorta: Role of Nitric Oxide (NO) Formation in Smooth Muscle. Biochem. Pharmacol. 2004, 67, 1203–1214. [CrossRef][PubMed] 72. Veras, R.C.; Rodrigues, K.G.; Alustau, M.D.C.; Araújo, I.G.A.; de Barros, A.L.B.; Alves, R.J.; Nakao, L.S.; Braga, V.A.; Silva, D.F.; de Medeiros, I.A. Participation of Nitric Oxide Pathway in the Relaxation Response Induced by E-Cinnamaldehyde Oxime in Superior Mesenteric Artery Isolated from Rats. J. Cardiovasc. Pharmacol. 2013, 62, 58–66. [CrossRef] 73. Dantas, B.P.V.; Ribeiro, T.P.; Assis, V.L.; Furtado, F.F.; Assis, K.S.; Alves, J.S.; Silva, T.M.S.; Camara, C.A.; França-Silva, M.S.; Veras, R.C.; et al. Vasorelaxation Induced by a New Naphthoquinone-Oxime Is Mediated by NO-SGC-CGMP Pathway. Molecules 2014, 19, 9773–9785. [CrossRef] 74. Oresmaa, L.; Kotikoski, H.; Haukka, M.; Oksala, O.; Pohjala, E.; Vapaatalo, H.; Moilanen, E.; Vainiotalo, P.; Aulaskari, P. Synthesis, Ocular Effects, and Nitric Oxide Donation of Imidazole Amidoximes. Eur. J. Med. Chem. 2006, 41, 1073–1079. [CrossRef] Molecules 2019, 24, 2470 19 of 19

75. Oresmaa, L.; Kotikoski, H.; Haukka, M.; Oksala, O.; Pohjala, E.; Vapaatalo, H.; Vainiotalo, P.; Aulaskari, P. Synthesis and Ocular Effects of Imidazole Nitrolic Acid and Amidoxime Esters. Bioorg. Med. Chem. Lett. 2006, 16, 2144–2147. [CrossRef]

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).