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 O 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.