S S symmetry

Review Unsubstituted Oximes as Potential Therapeutic Agents

Alicja K. Surowiak 1 , Stanisław Lochy ´nski 1,2 and Daniel J. Strub 1,*

1 Department of Chemical Biology and Bioimaging, Wroclaw University of Science and Technology, Wyb. Wyspia´nskiego27, 50-370 Wroclaw, Poland; [email protected] (A.K.S.); [email protected] (S.L.) 2 Institute of Cosmetology, Wroclaw College of Physiotherapy, T. Ko´sciuszki4, 50-029 Wrocław, Poland * Correspondence: [email protected]; Tel.: +48-71-320-2010



Received: 18 February 2020; Accepted: 24 March 2020; Published: 5 April 2020


Abstract: Oximes, which are highly bioactive molecules, have versatile uses in the medical sector and have been indicated to possess biological activity. Certain oximes exist in nature in plants and animals, but they are also obtained by chemical synthesis. Oximes are known for their anti-inflammatory, antimicrobial, antioxidant and anticancer activities. Moreover, they are therapeutic agents against organophosphate (OP) poisoning. Two oximes are already commonly used in therapy. Due to these abilities, new oxime compounds have been synthesized, and their biological activity has been verified. Often, modification of carbonyl compounds into oximes leads to increased activity. Nevertheless, in some cases, oxime activity is connected to the activity of the substrate. Recent works have revealed that new oxime compounds can demonstrate such functions and thus are considered to be potential drugs for pathogenic diseases, as adjuvant therapy in various types of cancer and inflammation and as potential next-generation drugs against OP poisoning.

Keywords: oximes; OP poisoning; antimicrobial; biological activity

1. Introduction The progressive and rampant development of the world, technological advances, overpopulation and environmental issues may cause many threats to human health. We are facing serious problems with a growing number of cancer-related and pathogenic diseases that cannot be effectively treated in traditional ways. Other detrimental factors are dangers from the development of agriculture, especially fertilization and the use of pesticides. The exposure to organophosphates (OPs) results in poisoning, and untreated OPs can lead to death. Obviously, the grand developments in medicine in recent years are undeniable, but drug alternatives have yet to be sought. Research is largely inspired by substances that occur in nature. Since 1960s plant oximes are known as one of the precursors of secondary metabolites in plants both aliphatic and aromatic forms. The majority of oximes are produced by one of the CYP79 family member—cytochrome P450. All flowering plants possessing CYP79 blueprint are, theoretically, able to produce oximes. These metabolites are often elements of the protective systems of plants that act in their defense against herbivores and pests in particular as intermediates in cyanogenic glycosides formation. Most of plant oximes are excreted as volatiles, only those that are converted into glycosides are stored in the plant. Oximes of natural origin often possess biological activities. Their presence in the biological sample might be omitted: oximes are intermediates for biosynthesis of other metabolites and their concentration is often low. [1]. Oximes in animals are, among other things, part of the olfactory communication between the animals. Oximes occur in nature as elements of metabolic pathways and are part of the enzymatic oxidation of amino acids and products of its decarboxylation. Two isomers are possible due to specificity of the C=N double bond; there are two

Symmetry 2020, 12, 575; doi:10.3390/sym12040575 www.mdpi.com/journal/symmetry SymmetrySymmetry 20202020,, 1212,, x 575 FOR PEER REVIEW 2 2of of 17 17 specificity of the C=N double bond; there are two stereoisomeric forms according to the E/Z E Z E configurationstereoisomeric [2]. forms E isomers according of tooximes the / areconfiguration more biologically [2]. isomers active ofthan oximes Z isomers. are more Moreover biologically in Z metabolicactive than processes,isomers. certain Moreover isomers in metabolic and a mixture processes, of both certain forms isomers are obtained. and a mixture It is ofpossible both forms that E Z chemicalare obtained. conversion It is possible E-isomer that chemicalto Z-isomer conversion in enzyme-isomer catalyzed to -isomer reaction in enzyme takes place catalyzed [1]. reactionDuring chemicaltakes place synthesis, [1]. During both chemicalstereoisomers synthesis, are obtained, both stereoisomers most of which are can obtained, be separated most of completely which can [3]. be Theseparated oxime completelymoiety can [ 3be]. Thebiotransformed, oxime moiety for can exam be biotransformed,ple, during oxidation for example, or reduction. during The oxidation most importantor reduction. property The most of oximes important is their property ability ofto oximescomplex is with their metals, ability which to complex makes with them metals, suitable which for themakes role themof potential suitable therapeutic for the role agents of potential as inhibitors therapeutic of metalloenzymes agents as inhibitors [4]. Another of metalloenzymes aspect is the poor [4]. waterAnother solubility aspect of is oximes, the poor but water a property solubility that of is oximes,obligatory but to a mark property a compound that is obligatory as a potential to mark drug. a Therefore,compound many as a potential researchers drug. have Therefore, modified many existi researchersng oximes have to improve modified their existing water oximes solubility. to improve One suchtheir modification water solubility. has Onebeen such presented modification by Okolotow has beenicz presentedet al., who by obtained Okolotowicz one amidine-oxime et al., who obtained with excellentone amidine-oxime water solubility with excellent (300 mg/mL). water solubility Oximes (300can mgbe/ mL).formed Oximes through canbe a formedfusion throughstrategy. a Implementingfusion strategy. reactive Implementing C=O groups reactive and electron C=O groups pair donator and electron into biomolecules pair donator is into also biomolecules one of oximes is featuresalso one [5]. of oximesMoreover, features they [assume5]. Moreover, a second- they and assume next generation a second- and catalyst next role generation in bioconjugation catalyst role [6]. in Thebioconjugation aspect that [6should]. The aspectbe taken that under should consideration be taken under for considerationthe application for of the oximes application as drugs of oximes is its cytotoxicity.as drugs is its On cytotoxicity. the one side On cytotoxicity the one side of cytotoxicityoximes might of oximescause side might effects cause of sidecertain eff ectstherapies, of certain on thetherapies, other side on cytotoxic the other activity side cytotoxic allows one activity to consid allowser oximes one to consideras potential oximes anticancer as potential agents anticancer[4]. Many oximesagents [are4]. already Many oximes known are as alreadytherapeutic known agents. as therapeutic This is why agents. we have This decided is why to we review have decidedthe recent to informationreview the recentabout informationunsubstituted about oximes, unsubstituted their anti-inflammatory, oximes, their anti-inflammatory, antimicrobial, antioxidant antimicrobial, and anticancerantioxidant activities, and anticancer and their activities, role against and theirOP poisoning. role against OP poisoning. 2. The Anti-Inflammatory Activity 2. The Anti-Inflammatory Activity Anti-inflammatory activity has been indicated for various oximes with diverse skeletons. The Park Anti-inflammatory activity has been indicated for various oximes with diverse skeletons. The group reported that steroidal antidrugs with the C-16,17-isoxazoline ring system—oxime derivatives Park group reported that steroidal antidrugs with the C-16,17-isoxazoline ring system—oxime (Figure1) had a high binding a ffinity with no suppressive effects. Moreover, nitric oxide (NO) derivatives (Figure 1) had a high binding affinity with no suppressive effects. Moreover, nitric oxide production was blocked. Many pathophysiological events are associated with production of NO. It is (NO) production was blocked. Many pathophysiological events are associated with production of also a response to proinflammatory cytokines. Moreover both oxime derivatives presented the ability NO. It is also a response to proinflammatory cytokines. Moreover both oxime derivatives presented to bind to the glucocorticoid receptor of liver cytosol, which might indicate ability to exert biological the ability to bind to the glucocorticoid receptor of liver cytosol, which might indicate ability to exert activity [7]. biological activity [7].

FigureFigure 1.1. Fluorinated oxime derivatives with with the the C-16, C-16,17-isoxazoline17-isoxazoline ring ring system. system. (a) (a )with with methoxy methoxy group and (b) with hydroxyl group.group and (b) with hydroxyl group.

Additionally,Additionally, one one oxime oxime synthetized synthetized by by Li Liwas was found found to be to a be potent a potent compound compound in blocking in blocking NO (ICNO50 (IC= 506.66= 6.66µM) µandM) andinterleukina interleukina 6 (IL-6; 6 (IL-6; IC50 IC 50= =5.075.07 µM)µM) production. production. IL-6 IL-6 is isone one of of the the proinflammatoryproinflammatory cytokines. cytokines. [8]. [8]. The The results results of the of theTharini Tharini and andSangeetha Sangeetha study study indicate indicate that that3,3- dimethyl-2,6-dimethylpiperidine-4-one3,3-dimethyl-2,6-dimethylpiperidine-4-one oxime oxime (Figure (Figure 2) 2)has has severe severe general anti-inflammatoryanti-inflammatory activityactivity in in contrast contrast to to the the ty typicalpical drug drug dexamethasone [9]. [9].

Symmetry 2020, 12, x FOR PEER REVIEW 2 of 17 specificity of the C=N double bond; there are two stereoisomeric forms according to the E/Z configuration [2]. E isomers of oximes are more biologically active than Z isomers. Moreover in metabolic processes, certain isomers and a mixture of both forms are obtained. It is possible that chemical conversion E-isomer to Z-isomer in enzyme catalyzed reaction takes place [1]. During chemical synthesis, both stereoisomers are obtained, most of which can be separated completely [3]. The oxime moiety can be biotransformed, for example, during oxidation or reduction. The most important property of oximes is their ability to complex with metals, which makes them suitable for the role of potential therapeutic agents as inhibitors of metalloenzymes [4]. Another aspect is the poor water solubility of oximes, but a property that is obligatory to mark a compound as a potential drug. Therefore, many researchers have modified existing oximes to improve their water solubility. One such modification has been presented by Okolotowicz et al., who obtained one amidine-oxime with excellent water solubility (300 mg/mL). Oximes can be formed through a fusion strategy. Implementing reactive C=O groups and electron pair donator into biomolecules is also one of oximes features [5]. Moreover, they assume a second- and next generation catalyst role in bioconjugation [6]. The aspect that should be taken under consideration for the application of oximes as drugs is its cytotoxicity. On the one side cytotoxicity of oximes might cause side effects of certain therapies, on the other side cytotoxic activity allows one to consider oximes as potential anticancer agents [4]. Many oximes are already known as therapeutic agents. This is why we have decided to review the recent information about unsubstituted oximes, their anti-inflammatory, antimicrobial, antioxidant and anticancer activities, and their role against OP poisoning.

2. The Anti-Inflammatory Activity Anti-inflammatory activity has been indicated for various oximes with diverse skeletons. The Park group reported that steroidal antidrugs with the C-16,17-isoxazoline ring system—oxime derivatives (Figure 1) had a high binding affinity with no suppressive effects. Moreover, nitric oxide (NO) production was blocked. Many pathophysiological events are associated with production of NO. It is also a response to proinflammatory cytokines. Moreover both oxime derivatives presented the ability to bind to the glucocorticoid receptor of liver cytosol, which might indicate ability to exert biological activity [7].

Figure 1. Fluorinated oxime derivatives with the C-16,17-isoxazoline ring system. (a) with methoxy group and (b) with hydroxyl group.

Additionally, one oxime synthetized by Li was found to be a potent compound in blocking NO (IC50 = 6.66 µM) and interleukina 6 (IL-6; IC50 = 5.07 µM) production. IL-6 is one of the proinflammatory cytokines. [8]. The results of the Tharini and Sangeetha study indicate that 3,3- dimethyl-2,6-dimethylpiperidine-4-oneSymmetry 2020, 12, 575 oxime (Figure 2) has severe general anti-inflammatory3 of 17 activity in contrast to the typical drug dexamethasone [9].

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Symmetry 2020, 12, x FOR FigurePEER REVIEW 2. 3,3-Dimethyl-2,6-dimethylpiperidine-4-one oxime. 3 of 17 Figure 2. 3,3-Dimethyl-2,6-dimethylpiperidine-4-one oxime. Zeferino-Diaz and coworkersFigure 2. 3,3-Dimethyl-2,6-dimethylpiperidine-4-one recently presented research onoxocholestane oxime. oxime diosgenin derivativesZeferino-Diaz (Figure 3and) as coworkers potential anti-inflammatoryrecently presented drugs.research In onin oxocholestane vivo studies theiroxime compounds diosgenin derivativesZeferino-Diaz (Figure 3) asand potential coworkers anti-inflammatory recently presented drugs. research In inon vivo oxocholestane studies their oxime compounds diosgenin have havederivatives been indicated (Figure to 3) reduceas potential inflammation anti-inflammatory and edema drugs. In triggered in vivo studies in mice their ear. compounds The expression have of been indicated to reduce inflammation and edema triggered in mice ear. The expression of proinflammatorybeen indicated genes to reduce such as inflammation tumor necrosis and factor edem (TNF-a triggeredα), prostaglandin-endoperoxide in mice ear. The expression synthase of 2 (COX-2)proinflammatoryproinflammatory and IL-6, genes with genes macrophage such such as as tumor tumor migration necrosis necrosis inhibitory factor (TNF- (TNF- factorαα), ),prostaglandin-endoperoxide prostaglandin-endoperoxide (MIF) was repressed by the synthase three synthase most 2active (COX-2)2 (COX-2) oximes and [and 10IL-6,]. IL-6, with with macrophage macrophage migration migration inhibitoryinhibitory factor factor (MIF) (MIF) was was repressed repressed by the by three the three mostmost active active oximes oximes [10]. [10].

Figure 3. Oxocholestane oxime diosgenin derivatives. (a) with acetyl group (b) with hydroxyl Figure 3. Oxocholestane oxime diosgenin derivatives. (a) with acetyl group (b) with hydroxyl group, Figure 3. Oxocholestane oximegroup, diosgenin and (c) derivatives. ketoxime derivative (a) with acetyl group (b) with hydroxyl and (c) ketoxime derivative. group, and (c) ketoxime derivative In their research Liu and colleagues presented in vivo activity of 6-bromoindirubin-3′-oxime In their research Liu and colleagues presented in vivo activity of 6-bromoindirubin-3 -oxime (FigureIn their 4)research on the Liuinflammatory and colleagues reaction. presented They analin vivoyzed activityresponse of to6-bromoindirubin-3 mastitis induced 0by′-oxime (Figure4) on the inflammatory reaction. They analyzed response to mastitis induced by (Figurelipopolysaccharide 4) on the inflammatory and signals of reaction.inflammation They in analmouseyzed mammary response epithelial to mastitis cells (MMECs). induced by lipopolysaccharidePretreatment with and tested signals oxime of led inflammation to downregula intion mouse of the mammaryexpression of epithelial the proinflammatory cells (MMECs). lipopolysaccharide and signals of inflammation in mouse mammary epithelial cells (MMECs). Pretreatmentfactors and with reduced tested infla oximemmatory led lesions to downregulation [11]. of the expression of the proinflammatory Pretreatment with tested oxime led to downregulation of the expression of the proinflammatory factors and reduced inflammatory lesions [11]. factors and reduced inflammatory lesions [11].

Figure 4. 6-Bromoindirubin-3′-oxime.

Kasare et al. presented studies involving protein denaturation inhibition bioassay of bovine serum albumin to examine if proteinFigure is 4. protected 6-Bromoindirubin-3 from denaturation.0′-oxime.-oxime. Both tested ligands (Figure 5) acquire remarkable anti-inflammatory activity in comparison to diclofenac sodium, achieving values ofKasare IC50 46.76 etet al.al. µM/mL presented presented and 55.77 studies studies µM/mL involving involving respectively protein protein [12]. denaturation denaturation inhibition inhibition bioassay bioassay of bovine of bovine serum serumalbumin albumin to examine to examine if protein if protein is protected is protected from denaturation. from denaturation. Both tested Both ligands tested ligands (Figure 5(Figure) acquire 5) acquireremarkable remarkable anti-inflammatory anti-inflammatory activity activity in comparison in comparison to diclofenac to diclofenac sodium, sodium, achieving achieving values ofvalues IC50 of46.76 IC50µ 46.76M/mL µM/mL and 55.77 andµ 55.77M/mL µM/mL respectively respectively [12]. [12].

Figure 5. Azo-azomethine based oxime derivatives: (a) with methyl group and (b) with methoxy group

Hassan et al. presented results of anti-inflammatory activity of various novel quinoline hybrids. ThreeFigure of 5.compounds Azo-azomethine (Figure based 6) oximepossessing derivatives: oxime (a) moiety with methyl presented group excellent and (b) with general methoxy anti- inflammatory activity in in vivo studies, using paw edema in rats induced by carrageenan injection, group

Hassan et al. presented results of anti-inflammatory activity of various novel quinoline hybrids. Three of compounds (Figure 6) possessing oxime moiety presented excellent general anti- inflammatory activity in in vivo studies, using paw edema in rats induced by carrageenan injection,

Symmetry 2020, 12, x FOR PEER REVIEW 3 of 17

Figure 2. 3,3-Dimethyl-2,6-dimethylpiperidine-4-one oxime.

Zeferino-Diaz and coworkers recently presented research on oxocholestane oxime diosgenin derivatives (Figure 3) as potential anti-inflammatory drugs. In in vivo studies their compounds have been indicated to reduce inflammation and edema triggered in mice ear. The expression of proinflammatory genes such as tumor necrosis factor (TNF-α), prostaglandin-endoperoxide synthase 2 (COX-2) and IL-6, with macrophage migration inhibitory factor (MIF) was repressed by the three most active oximes [10].

Figure 3. Oxocholestane oxime diosgenin derivatives. (a) with acetyl group (b) with hydroxyl group, and (c) ketoxime derivative

In their research Liu and colleagues presented in vivo activity of 6-bromoindirubin-3′-oxime (Figure 4) on the inflammatory reaction. They analyzed response to mastitis induced by lipopolysaccharide and signals of inflammation in mouse mammary epithelial cells (MMECs). Pretreatment with tested oxime led to downregulation of the expression of the proinflammatory factors and reduced inflammatory lesions [11].

Figure 4. 6-Bromoindirubin-3′-oxime.

Kasare et al. presented studies involving protein denaturation inhibition bioassay of bovine serum albumin to examine if protein is protected from denaturation. Both tested ligands (Figure 5) Symmetryacquire remarkable2020, 12, 575 anti-inflammatory activity in comparison to diclofenac sodium, achieving values4 of 17 of IC50 46.76 µM/mL and 55.77 µM/mL respectively [12].

FigureFigure 5. 5.Azo-azomethine Azo-azomethine based based oxime oxime derivatives: derivatives: (a) with(a) with methyl methyl group group and (andb) with (b) with methoxy methoxy group. group SymmetryMohassab 2020, 12, etx FOR al. presentedPEER REVIEW results of anti-inflammatory activity of various novel quinoline hybrids.4 of 17 ThreeSymmetryHassan of 2020 compounds, et12 , al.x FOR presented (FigurePEER REVIEW6 results) possessing of anti-inflammatory oxime moiety presented activity excellentof various general novel quinoline anti-inflammatory hybrids.4 of 17 activityThreecompared of in incompoundsto vivoindomethacin.studies, (Figure using Observed paw6) possessing edema percentage in ratsox ofime induced edema moiety inhibition by carrageenanpresented were excellent injection,100%, 101% general compared and 111%anti- to compared to indomethacin. Observed percentage of edema inhibition were 100%, 101% and 111% indomethacin.inflammatoryrespectively [13]. activity Observed in in percentage vivo studies, of edema using inhibition paw edema were in 100%,rats induced 101% and by 111%carrageenan respectively injection, [13]. respectively [13].

Figure 6. Quinoline 1,2,4-triazole/oxime derivatives: a) and b) with phenyl group linked to triazole FigureFigure 6. 6.Quinoline Quinoline 1,2,4-triazole 1,2,4-triazole/oximering; (c) /withoxime allyl derivatives:derivatives: group linked (a)a, band )to with triazole b) with phenyl ringphenyl group (c) group linked linked to triazole to triazole ring; (c) with allyl group linkedring; to triazole (c) with ring allyl (c ).group linked to triazole ring (c) With the same method Abd-Ellah and coworkers tested 1,3,4-oxadiazole/oxime derivatives as a resultWith on of thethe the samesame hybrids methodmethod obtained Abd-EllahAbd-Ellah 96.67% and reduction coworkers in edema[14]. tested 1,3,4-oxadiazole1,3,4-oxadiazole/oxime /oxime derivatives as a result onon ofof thethe hybridshybrids obtainedobtained 96.67%96.67% reductionreduction inin edemaedema[14]. [14]. 3. The Antimicrobial Activity 3. The Antimicrobial Activity Cytotoxicity is one property of oximes; thus, oximes are therapeutic agents for bacterial, fungal Cytotoxicity is one property of oximes; thus, oximes are therapeutic agents for bacterial, fungal and viralCytotoxicity infections. is one Nocardicin property Aof (Figureoximes; 7) thus, is the oxim firstes βare-lactam therapeutic antibiotic agents isolated for bacterial, from Nocardia fungal and viral infections. Nocardicin A (Figure7) is the first β-lactam antibiotic isolated from Nocardia uniformisand viral [15].infections. The presence Nocardicin of the A oxime (Figure moiety 7) is inthe this first antibiotic β-lactam makes antibiotic it less isolated stable to from β-lactamases Nocardia uniformis [15]. The presence of the oxime moiety in this antibiotic makes it less stable to β-lactamases [16]. [16].uniformis [15]. The presence of the oxime moiety in this antibiotic makes it less stable to β-lactamases [16].

Figure 7. Nocardicin A. Figure 7. Nocardicin A. ModificationModification of of already already existing existing antibiotics antibiotics into into oximes oximes is a subject is a subject that has that appeared has appeared in research in researchover Modificationthe overyears. the Good years. of already Goodexamples existing examples of antibioticssuch of suchmodifi into modificationscations oximes are is a are subjectthose those in that in cephalosporin cephalosporin has appeared antibiotics.in antibiotics. research Improvementover the years. of waterGood solubilityexamples ofof oximes such modifican becations achieved are by those a mo dificationin cephalosporin of oxime antibiotics.moiety by attainingImprovement their ofether water and solubility ester derivatives. of oximes Ceftobipcan be achievedrole medocaril by a mo (Figuredification 8b) isof aoxime fifth-generation moiety by cephalosporinattaining their antibioticether and [17]. ester Prodrug derivatives. of ceftobiprole Ceftobiprole with medocaril satisfactory (Figure water 8b) solubility is a fifth-generation is shown in (Figurecephalosporin 8a). It isantibiotic a β-lactam [17]. antibacterial Prodrug of agent ceftobiprole from one with of satisfactorythe cepham waterseries solubilityof cephalosporins. is shown Itsin antibacterial(Figure 8a). It activity is a β-lactam is connected antibacterial with the agent ability from to bindone ofto thepenicillin-binding cepham series proteinsof cephalosporins. (PBPs) [18]. Its antibacterial activity is connected with the ability to bind to penicillin-binding proteins (PBPs) [18].

Symmetry 2020, 12, 575 5 of 17

Improvement of water solubility of oximes can be achieved by a modification of oxime moiety by attaining their ether and ester derivatives. Ceftobiprole medocaril (Figure8b) is a fifth-generation cephalosporin antibiotic [17]. Prodrug of ceftobiprole with satisfactory water solubility is shown in (Figure8a). It is a β-lactam antibacterial agent from one of the cepham series of cephalosporins. Its antibacterialSymmetry 2020 activity, 12, x FOR is PEER connected REVIEW with the ability to bind to penicillin-binding proteins (PBPs)5 of [18 17].

Figure 8. (a) Prodrug of ceftobiprole and (b) ceftobiprole medocaril. Figure 8. (a) Prodrug of ceftobiprole and (b) ceftobiprole medocaril. Paulsen and colleagues synthetized (+)-N-6-hydroxyagelasine D, the enantiomer of a well- Paulsen and colleagues synthetized (+)-N-6-hydroxyagelasine D, the enantiomer of a well-known known secondary metabolite from marine sponges—(−)-ageloxime D, [19]. The authors revealed that secondary metabolite from marine sponges—( )-ageloxime D, [19]. The authors revealed that the the previously proposed structures of (-)-ageloxim− e D extracted from a natural product [20] are in previously proposed structures of (-)-ageloxime D extracted from a natural product [20] are in fact fact not an oxime, as the spectral data did not match. However, (-)-ageloxime can be obtained by a not an oxime, as the spectral data did not match. However, (-)-ageloxime can be obtained by a basic basic hydrolysis of agelasine D. (−)-Ageloxime D inhibits biofilm formation from Gram-positive hydrolysis of agelasine D. ( )-Ageloxime D inhibits biofilm formation from Gram-positive bacteria bacteria Staphylococcus epidermis− [19] but is unable to inhibit the growth of planktonic bacteria (MIC µ Staphylococcus> 45 µM) [20]. epidermis Proposed[19] but(+)-N is-6-hydroxyagelasine unable to inhibit the D growth bromide of planktonic also possesses bacteria the (MICability> to45 reduceM) [20 ]. Proposedbiofilm (formation+)-N-6-hydroxyagelasine of Staphylococcus Depidermidis bromide by also 90% possesses at 63 µM the [19]. ability to reduce biofilm formation of StaphylococcusMany antimicrobial epidermidis activeby 90% compounds at 63 µM[ are19 modified]. to resemble oximes to increase their activity. TheMany compound antimicrobial 5,7-dimethoxyflavone active compounds carbonyl are modified was modified to resemble into an oximes oxime,to and increase this modification their activity. Theamplified compound its antifungal 5,7-dimethoxyflavone functions [21]. carbonyl In their research, was modified Min et al. into synthesized an oxime, new and oxime this modification esters that amplifiedhad antifungal its antifungal activity. functions In addition, [21 they]. In also their considered research, the Min E, Z et stereoisomer al. synthesized substrates new oximeof 3-caren- esters that5-one had oxime antifungal (Figure activity. 9a,b), which In addition, were separated they also for considered the first time. the BothE, Z stereoisomersstereoisomer had substrates relative of 3-caren-5-oneinhibition rates oxime above (Figure 50% 9againsta,b), which Physalospora were separated piricola [22]. for the first time. Both stereoisomers had relative inhibition rates above 50% against Physalospora piricola [22].

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Symmetry 2020, 12, 575 6 of 17

Figure 9. 3-Caren-5-one oximes: E-isomer (a) and Z-isomer (b). Figure 9. 3-Caren-5-one oximes: E-isomer (a) and Z-isomer (b). Synthetic naringenin, a flavonoid that naturally occurs in grapefruits, was modified to contain oximesSynthetic by Kozłowska naringenin, et al. Foura flavonoid derivatives that havenaturally indicated occurs to havein grapef antibacterialruits, was activity. modified The to minimal contain inhibitoryoximes by concentration Kozłowska et (MIC) al. Four against derivativeStaphylococcuss have indicated aureus was to belowhave antibacterial 100 µg/mL. Twoactivity. oximes The (Figureminimal 10 )inhibitory showed MIC concentration values against (MIC)Staphylococcus against Staphylococcus aureus and Bacillus aureussubtilis was belowbelow 100 12.5 µg/mL.µg/mL [Two23]. Inoximes comparison (Figure to 10) naringenin showed MIC itself, values which against had no Staphylococcus antimicrobial aureus activity, and theBacillus results subtilis obtained below were 12.5 satisfactoryµg/mL [23]. [24 In]. comparison to naringenin itself, which had no antimicrobial activity, the results Symmetry 2020, 12, x FOR PEER REVIEW 7 of 17 obtained were satisfactory [24].

OH O

O O O O

OH N OH N OH OH (a) (b)

Figure 10. ((aa)) 7- 7-OO-isopropyl-isopropyl naringenin naringenin oxime and ( b) 7,4 ′0-di--di-OO-isopropyl-isopropyl naringenin naringenin oxime. oxime.

Additionally, Xu observed that in chalcone derivativesderivatives oxime moiety enhances antimicrobial activity [25]. [25]. The The presence presence of of oxime moiety in co compoundmpound (Figure 11b)11b) resulted with a MIC value of ≤128128 µg/mLµg/mL [[26]26] whereaswhereas compound compound (Figure (Figure 11 a)11a) had had a MIC a MIC value value of 150 ofµ 150g/mL µg/mL [27] against [27] againstB. subtilis B.. ≤ subtilisSimilar. Similar difference difference was observed was observed for both for of both compounds of compounds against againstA. niger A. nigerobtained obtained MIC MIC values values was was300 µ300g/mL µg/mL [27] and[27] and256 ≤µ256g/mL µg/mL (oxime) (oxime) [26]. [26]. ≤

Figure 11. Chalcone fluorinated derivatives: (a) ketone (b) oxime

Kozioł et al. presented the results (MIC values) of experiments performed on synthesized oximes on bacteria. Among nine oximes, three (Figure 12) presented satisfactory antibacterial activity. Oximes (a) and (c) had the best antibacterial activity against Staphylococcus aureus, whereas oxime (b) presented the best antibacterial activity. Their MIC values were 100 µg/mL [28].

Figure 12. (a) (-)-Menthone oxime; (b) (+)-Carvone oxime and (c) (+)-Pulegone oxime.

The antiviral activity of E,Z isomers of Janus-type nucleoside against Herpes simplex virus-I (HSV- 1) were tested by Liu et al. Most oximes demonstrated improved anti-HSV-1 activity compared to the Janus-type nucleosides. Among the oximes, exquisite anti-HSV-1 activity was displayed by two compounds (Figure 13), both had low IC50 values of 0.05 and 0.04 µg/mL. Moreover the compounds shown in Figure 13 also presented antiviral activity against distinct viruses as Herpes simplex virus-II (HSV-2), influenza viruses (H3N2), coxsackievirus B3 (CVB3), Hepatitis B virus (HBV), Hepatitis B virus (HCV) and Human papillomavirus (HPV) [29].

Symmetry 2020, 12, x FOR PEER REVIEW 7 of 17 Symmetry 2020, 12, x FOR PEER REVIEW 7 of 17

OH O OH O O O O O O O O O

OH N OH N OH N OH OH N OH (a)OH (b)OH (b) (a) Figure 10. (a) 7-O-isopropyl naringenin oxime and (b) 7,4′-di-O-isopropyl naringenin oxime. Figure 10. (a) 7-O-isopropyl naringenin oxime and (b) 7,4′-di-O-isopropyl naringenin oxime. Additionally, Xu observed that in chalcone derivatives oxime moiety enhances antimicrobial Additionally, Xu observed that in chalcone derivatives oxime moiety enhances antimicrobial activity [25]. The presence of oxime moiety in compound (Figure 11b) resulted with a MIC value of activity [25]. The presence of oxime moiety in compound (Figure 11b) resulted with a MIC value of ≤128 µg/mL [26] whereas compound (Figure 11a) had a MIC value of 150 µg/mL [27] against B. ≤128 µg/mL [26] whereas compound (Figure 11a) had a MIC value of 150 µg/mL [27] against B. Symmetrysubtilis. Similar2020, 12, 575difference was observed for both of compounds against A. niger obtained MIC values7 of 17 subtilis. Similar difference was observed for both of compounds against A. niger obtained MIC values was 300 µg/mL [27] and ≤256 µg/mL (oxime) [26]. was 300 µg/mL [27] and ≤256 µg/mL (oxime) [26].

Figure 11. Chalcone fluorinated derivatives: (a) ketone (b) oxime FigureFigure 11. 11.Chalcone Chalcone fluorinatedfluorinated derivatives:derivatives: ((a)a) ketoneketone ((b)b) oxime.oxime KoziołKozioł et al. presented presented the results (MIC values) of experiments experiments performed on synthesized oximes Kozioł et al. presented the results (MIC values) of experiments performed on synthesized oximes on bacteria.bacteria. AmongAmong nine nine oximes, oximes, three three (Figure (Figure 12) presented 12) presented satisfactory satisfactory antibacterial antibacterial activity. activity. Oximes on bacteria. Among nine oximes, three (Figure 12) presented satisfactory antibacterial activity. (a)Oximes and (c) (a) had and the (c) besthad antibacterialthe best antibacterial activity against activityStaphylococcus against Staphylococcus aureus, whereas aureus oxime, whereas (b) presentedoxime (b) Oximes (a) and (c) had the best antibacterial activity against Staphylococcus aureus, whereas oxime (b) thepresented best antibacterial the best antibacterial activity. Their activity. MIC Their values MIC were values 100 µ gwere/mL 100 [28]. µg/mL [28]. presented the best antibacterial activity. Their MIC values were 100 µg/mL [28].

Figure 12. (a) (-)-Menthone oxime; (b)(+)-Carvone oxime and (c)( +)-Pulegone oxime. Figure 12. (a) (-)-Menthone oxime; (b) (+)-Carvone oxime and (c) (+)-Pulegone oxime. Figure 12. (a) (-)-Menthone oxime; (b) (+)-Carvone oxime and (c) (+)-Pulegone oxime. The antiviral activity of E,Z isomers of Janus-type nucleoside against Herpes simplex virus-I (HSV-1) The antiviral activity of E,Z isomers of Janus-type nucleoside against Herpes simplex virus-I (HSV- wereThe tested antiviral by Liu activity et al. Most of E,Z oximes isomers demonstrated of Janus-type improved nucleoside anti-HSV-1 against Herpes activity simplex compared virus-I (HSV- to the 1) were tested by Liu et al. Most oximes demonstrated improved anti-HSV-1 activity compared to the Janus-type1) were tested nucleosides. by Liu et al. Among Most oximes the oximes, demonstr exquisiteated improved anti-HSV-1 anti-HSV-1 activity activity was displayed compared by to two the Janus-type nucleosides. Among the oximes, exquisite anti-HSV-1µ activity was displayed by two compoundsJanus-type nucleosides. (Figure 13), bothAmong had the low oximes, IC50 values exquis of 0.05ite anti-HSV-1 and 0.04 g activity/mL. Moreover was displayed the compounds by two showncompounds in Figure (Figure 13 also 13), presentedboth had low antiviral IC50 values activity of against0.05 and distinct 0.04 µg viruses/mL. Moreover as Herpes the simplex compounds virus-II compounds (Figure 13), both had low IC50 values of 0.05 and 0.04 µg/mL. Moreover the compounds shown in Figure 13 also presented antiviral activity against distinct viruses as Herpes simplex virus-II (HSV-2),shown in influenza Figure 13 viruses also presented (H3N2), coxsackievirusantiviral activity B3 against (CVB3), distinctHepatitis viruses B virus as(HBV), HerpesHepatitis simplex virus-II B virus (HCV)(HSV-2), and influenza Human viruses papillomavirus (H3N2), coxsackievirus (HPV) [29]. B3 (CVB3), Hepatitis B virus (HBV), Hepatitis B virus Symmetry(HSV-2), 2020 influenza, 12, x FOR viruses PEER REVIEW (H3N2), coxsackievirus B3 (CVB3), Hepatitis B virus (HBV), Hepatitis B8 ofvirus 17 (HCV) and Human papillomavirus (HPV) [29]. (HCV) and Human papillomavirus (HPV) [29]. Cl Cl OH OH N N N N

N NH N NH

H3CO

(a) (b) FigureFigure 13. 13. (a()a ()(E)-4-Chloro-6-((4-(E)-4-Chloro-6-((4-(terttert-butyl)benzyl)amino)pyrimidine-butyl)benzyl)amino)pyrimidine-5-carbaldehyde-5-carbaldehyde oxime oxime and and(b) ((Eb)-4-Chloro-6-((2-methoxybenzyl)amino))(E)-4-Chloro-6-((2-methoxybenzyl)amino)pyrimidine-5-carbaldehydepyrimidine-5-carbaldehyde oxime. oxime.

ChanChan et al. tested tested antiviral antiviral activity activity of of indirubin-3 ′0-oxime-oxime (Figure (Figure 14)14) by by the the assessment assessment of of the the infectiousinfectious virus virus titers titers in in epithelial epithelial cells cells and and human human macrophages. macrophages. Viral Viral replication replication was was inhibited inhibited by by aboutabout 10-fold in H5N1 virus–infectedvirus–infected macrophagesmacrophages and and ATIs ATIs by by oxime oxime compared compared to to untreated untreated cells. cells. In Inthe the H1N1 H1N1 treatment treatment of virus–infected of virus–infected macrophages macrophages at 24 at h post-infection,24 h post-infection, as well as as well in infected as in infected ATIs at ATIs48 h post-infectionat 48 h post-infection similar results similar were results observed. were Additionally,observed. Additionally, viral matrix viral 1 protein matrix expression 1 protein in expression in H5N1 virus-infected macrophages was effectively suppressed. In vivo studies on mice have proven that indirubin-3′-oxime does not have a positive effect on survival and does not promote weight loss, despite that the reduction of expression and secretion of cytokine and chemokine is observed [30].

Figure 14. Indirubin-3′-oxime.

4. The Antioxidant Activity In addition to having anti-inflammatory activity, naringenin also revealed antioxidant properties. The modification of this compound into an oxime increased its antioxidant activity. The oxime is considered a radioprotector or an anticancer agent [31]. Another example of an oxime with a high antioxidant activity is an isoxanthohumol oxime (Figure 15). This compound has a 200 times higher activity than isoxanthohumol, which is comparable to ascorbic acid [32].

Figure 15. Isoxanthohumol oxime.

Kaur et al. evaluated the content of Anethum graveolens L. essential oil and its relationship to its antioxidant activity. Five parameters were tested. The carvone oxime has indicated to have good radical scavenging activity. For the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical the IC50 reached 0.31 mg/mL, for the hydroxyl radical the IC50 was 0.23 mg/mL and for the nitric oxide (NO) radical the IC50 was 0.31 mg/mL. The ferric reducing antioxidant power (FRAP) mean value was 196.88 mg/mL. The mean superoxide radical scavenging activity was 44.57 with an IC50 value of 0.31

Symmetry 2020, 12, x FOR PEER REVIEW 8 of 17 Symmetry 2020, 12, x FOR PEER REVIEW 8 of 17 Cl Cl Cl Cl OH OH N N OH N N OH N N N N N NH N NH N NH N NH

H3CO H3CO (a) (b) (a) (b) Figure 13. (a) (E)-4-Chloro-6-((4-(tert-butyl)benzyl)amino)pyrimidine-5-carbaldehyde oxime and (b) Figure 13. (a) (E)-4-Chloro-6-((4-(tert-butyl)benzyl)amino)pyrimidine-5-carbaldehyde oxime and (b) (E)-4-Chloro-6-((2-methoxybenzyl)amino)pyrimidine-5-carbaldehyde oxime. (E)-4-Chloro-6-((2-methoxybenzyl)amino)pyrimidine-5-carbaldehyde oxime. Chan et al. tested antiviral activity of indirubin-3′-oxime (Figure 14) by the assessment of the Chan et al. tested antiviral activity of indirubin-3′-oxime (Figure 14) by the assessment of the infectious virus titers in epithelial cells and human macrophages. Viral replication was inhibited by infectious virus titers in epithelial cells and human macrophages. Viral replication was inhibited by about 10-fold in H5N1 virus–infected macrophages and ATIs by oxime compared to untreated cells. about 10-fold in H5N1 virus–infected macrophages and ATIs by oxime compared to untreated cells. InSymmetry the H1N12020, 12treatment, 575 of virus–infected macrophages at 24 h post-infection, as well as in infected8 of 17 In the H1N1 treatment of virus–infected macrophages at 24 h post-infection, as well as in infected ATIs at 48 h post-infection similar results were observed. Additionally, viral matrix 1 protein ATIs at 48 h post-infection similar results were observed. Additionally, viral matrix 1 protein expression in H5N1 virus-infected macrophages was effectively suppressed. In vivo studies on mice H5N1expression virus-infected in H5N1 virus-infected macrophages macrop was effectivelyhages was suppressed. effectivelyIn suppressed. vivo studies In onvivo mice studies have on proven mice have proven that indirubin-3′-oxime does not have a positive effect on survival and does not promote thathave indirubin-3 proven that0-oxime indirubin-3 does′ not-oxime have does a positive not have eff ecta positive on survival effect and on survival does not and promote does not weight promote loss, weight loss, despite that the reduction of expression and secretion of cytokine and chemokine is despiteweight thatloss, thedespite reduction that ofthe expression reduction andof expression secretion of and cytokine secretion and chemokineof cytokine isand observed chemokine [30]. is observed [30]. observed [30].

Figure 14. Indirubin-3′-oxime. FigureFigure 14.14. Indirubin-3Indirubin-30′-oxime. 4.4. The The Antioxidant Antioxidant Activity Activity 4. The Antioxidant Activity InIn additionaddition to to having having anti-inflammatory anti-inflammatory activity, acti naringeninvity, naringenin also revealed also antioxidantrevealed antioxidant properties. In addition to having anti-inflammatory activity, naringenin also revealed antioxidant properties.The modification The modification of this compound of this compound into an oxime into increasedan oxime increased its antioxidant its antioxidant activity. Theactivity. oxime The is properties. The modification of this compound into an oxime increased its antioxidant activity. The oximeconsidered is considered a radioprotector a radioprotector or an anticancer or an antica agentncer [31 agent]. Another [31]. Another example example of an oxime of an oxime with a with high oxime is considered a radioprotector or an anticancer agent [31]. Another example of an oxime with aantioxidant high antioxidant activity activity is an isoxanthohumol is an isoxanthohumol oxime oxime (Figure (Figure 15). This 15). compound This compound has a 200has times a 200 highertimes a high antioxidant activity is an isoxanthohumol oxime (Figure 15). This compound has a 200 times higheractivity activity than isoxanthohumol, than isoxanthohumol, which iswhich comparable is comparable to ascorbic to ascorbic acid [32 acid]. [32]. higher activity than isoxanthohumol, which is comparable to ascorbic acid [32].

Figure 15. Isoxanthohumol oxime. FigureFigure 15.15. IsoxanthohumolIsoxanthohumol oxime. Kaur et al. evaluated the content of Anethum graveolens L. essential oil and its relationship to its Kaur et al. evaluated evaluated the the content content of of AnethumAnethum graveolens graveolens L.L. essential essential oil oil and and its itsrelationship relationship to its to antioxidant activity. Five parameters were tested. The carvone oxime has indicated to have good itsantioxidant antioxidant activity. activity. Five Five parameters parameters were were tested. tested. The carvone The carvone oxime oxime has indicated has indicated to have to good have radical scavenging activity. For the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical the IC50 goodradical radical scavenging scavenging activity. activity. For the For 2,2-diphen the 2,2-diphenyl-1-picrylhydrazylyl-1-picrylhydrazyl (DPPH) (DPPH) free radical free radical the IC the50 reached 0.31 mg/mL, for the hydroxyl radical the IC50 was 0.23 mg/mL and for the nitric oxide (NO) ICreached50 reached 0.31 mg/mL, 0.31 mg /formL, the for hydroxyl the hydroxyl radical radical the IC the50 was IC50 0.23was mg/mL 0.23 mg and/mL for and the for nitric the nitricoxide oxide(NO) radical the IC50 was 0.31 mg/mL. The ferric reducing antioxidant power (FRAP) mean value was (NO)radical radical the IC the50 was IC50 0.31was mg/mL. 0.31 mg /ThemL. ferric Theferric reducing reducing antioxidant antioxidant power power (FRAP) (FRAP) mean mean value value was 196.88 mg/mL. The mean superoxide radical scavenging activity was 44.57 with an IC50 value of 0.31 was196.88 196.88 mg/mL. mg/ ThemL. mean The mean superoxide superoxide radical radical scavenging scavenging activity activity was 44.57 was with 44.57 an with IC50 an value IC50 ofvalue 0.31

of 0.31 mg/mL [33]. Bandeira et al. proved that organotellurium oximes have promising radical scavenging activity. Against the DPPH radical both compounds presented in Figure 16 had IC50 values of 5.12 0.71 mg/mL and 7.79 0.33 mg/mL, respectively. Both oximes have also been ± ± examined for their ability to reduce the 1-n-propyl-tetrazole complex with Fe3+(PTZ-Fe3+) complex in 2,20-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radicals and FRAP. The results showed an antioxidant activity similar to that demonstrated by trolox. The first oxime had a capacity of approximately 8 mM TE/g (ABTS) and 11 mM TE/g (FRAP). The second oxime had a capacity of approximately 7 mM TE/g (ABTS) and 14 mM TE/g (FRAP), which were similar to the control quercetin [34]. Symmetry 2020, 12, x FOR PEER REVIEW 9 of 17 Symmetry 2020, 12, x FOR PEER REVIEW 9 of 17 Symmetry 2020, 12, x FOR PEER REVIEW 9 of 17 mg/mL [33]. Bandeira et al. proved that organotellurium oximes have promising radical scavenging mg/mL [33]. Bandeira et al. proved that organotellurium oximes have promising radical scavenging activity.mg/mL [33].Against Bandeira the DPPH et al. radicalproved both that compoundsorganotellurium presented oximes in have Figure promising 16 had IC radical50 values scavenging of 5.12 ± activity. Against the DPPH radical both compounds presented in Figure 16 had IC50 values of 5.12 ± 0.71activity. mg/mL Against and the7.79 DPPH ± 0.33 radical mg/mL, both respectively. compounds Both presented oximes in have Figure also 16 been had ICexamined50 values forof 5.12their ± 0.71 mg/mL and 7.79 ± 0.33 mg/mL, respectively. Both oximes have also been examined for their 0.71 mg/mL and 7.79 ± 0.33 mg/mL, respectively. Both oximes3+ have3+ also been examined for their ability to reduce the 1-n-propyl-tetrazole complex with Fe 3+(PTZ-Fe 3+) complex in 2,2’-azino-bis(3- ability to reduce the 1-n-propyl-tetrazole complex with Fe3+(PTZ-Fe3+) complex in 2,2’-azino-bis(3- ethylbenzothiazoline-6-sulfonicability to reduce the 1-n-propyl-tetrazole acid) (ABTS) complex radica lswith and Fe FRAP.(PTZ-Fe The results) complex showed in 2,2’-azino-bis(3- an antioxidant ethylbenzothiazoline-6-sulfonic acid) (ABTS) radicals and FRAP. The results showed an antioxidant activityethylbenzothiazoline-6-sulfonic similar to that demonstrated acid) by (ABTS) trolox. radica The firstls and oxime FRAP. had The a capacity results of showed approximately an antioxidant 8 mM activity similar to that demonstrated by trolox. The first oxime had a capacity of approximately 8 mM TE/gSymmetryactivity (ABTS) 2020similar, 12and, 575to 11 that mM demonstrated TE/g (FRAP). by The trolox. second The oxime first oxime had a hadcapacity a capacity of approximately of approximately 7 mM 8 9TE/g mM of 17 TE/g (ABTS) and 11 mM TE/g (FRAP). The second oxime had a capacity of approximately 7 mM TE/g (ABTS)TE/g (ABTS) and 14 and mM 11 TE/g mM TE/g(FRAP), (FRAP). which The were second similar oxime to the had control a capacity quercetin of approximately [34]. 7 mM TE/g (ABTS) and 14 mM TE/g (FRAP), which were similar to the control quercetin [34].

Figure 16. Tellurium oxime derivatives: (a) 3-butyltellanyl- and (b) 4-butyltellanyl- FigureFigure 16.16. Tellurium oximeoxime derivatives:derivatives: ((a)a) 33-butyltellanyl--butyltellanyl- andand ((b)b) 4-butyltellanyl-.-butyltellanyl- Figure 16. Tellurium oxime derivatives: (a) 3-butyltellanyl- and (b) 4-butyltellanyl- Bensegueni et al. presented original work on antioxidant activity of aromatic oximes. Bensegueni etet al. al. presented presented original original work onwork antioxidant on antioxidant activity ofactivity aromatic of oximes. aromatic Outstanding oximes. OutstandingresultsBensegueni were obtainedresults et wereal. by presented oneobtained of the by oximesoriginal one of (Figure thework ox imes17on). Percentageantioxidant(Figure 17). of Percentageactivity DPPH inhibitionof of aromatic DPPH was inhibition oximes. 34.50 Outstanding results were obtained by one of the oximes (Figure 17). Percentage of DPPH inhibition± was1.56. 34.50 Additionally, ± 1.56. Additionally, in Cupric reducing in Cupric antioxidant reducing antioxidant capacity assay capacity (CUPRAC) assay (CUPRAC) with an A with50 = an2.60 A50 was 34.50 ± 1.56. Additionally, in Cupric reducing antioxidant capacity assay (CUPRAC) with an A±50 =0.16was 2.60 µ34.50 g±/ 0.16mL ± [1.56.µg/mL35]. Additionally, [35]. in Cupric reducing antioxidant capacity assay (CUPRAC) with an A50 = 2.60 ± 0.16 µg/mL [35].

Figure 17. 1H-indole-3-carbaldehyde oxime. Figure 17. 1H-indole-3-carbaldehyde oxime. Figure 17. 1H-indole-3-carbal1H-indole-3-carbaldehydedehyde oxime. Siddiqui and colleagues have tested 2,6-diphenylpiperidine-4-one oxime derivatives (Figure 18). Siddiqui and colleagues have tested tested 2,6-diphenyl 2,6-diphenylpiperidine-4-onepiperidine-4-one oxime oxime derivatives derivatives (Figure (Figure 18).18). The DPPHSiddiqui activity and colleagues was tested. have Both tested oximes 2,6-diphenyl presentedpiperidine-4-one antioxidant activity. oxime Compound derivatives (Figure (Figure 18b) 18). The DPPH activity was tested. Both oximes presen presentedted antioxidant activity. Compound (Figure 18b)18b) presentedThe DPPH better activity activity was tested.(IC50+ SEMBoth =oximes 4.53 ± 0.41presen µg/mL)ted antioxidant than other activity. oxime (IC Compound50 + SEM = (Figure11.13 ± 18b)0.17 presented better activity (IC (IC5050++ SEMSEM = =4.534.53 ± 0.410.41 µg/mL)µg/mL) than than other other oxime oxime (IC (IC50 +50 SEM+ SEM = 11.13= 11.13 ± 0.17 presented better activity (IC50+ SEM = 4.53 ± ±0.41 µg/mL) than other oxime (IC50 + SEM = 11.13 ± 0.17± µg/mL)µ [36]. 0.17µg/mL)g/ mL)[36]. [36].

Figure 18. 2,6-diphenylpiperidine-4-one oxime derivatives. With heptyl group (a) and with hydroxy Figure 18. 2,6-diphenylpiperidine-4-one oxime derivatives. With heptyl group (a) and with hydroxy FigureFigure 18.18. 2,6-diphenylpiperidine-4-oneand oxime methoxy derivatives.derivative groupss. (b)With With heptyl group (a) (a) and and with with hydroxy hydroxy and methoxy groups (b) and methoxy groups (b). and methoxy groups (b) 5. The Anticancer Activity 5. The Anticancer Activity Pregnenolone is an endogenic steroid and a precursor in the biosynthesis of steroid hormones. Pregnenolone is an endogenic steroid and a prec precursorursor in the biosynthesis of of steroid hormones. PregnenolonePregnenolone was modifiedis an endogenic to a benzylidene steroid and oxime a prec andursor two in other.the biosynthesis The derivatives of steroid were hormones. tested for Pregnenolone was modified modified to a benzylidene oxime and two other. The derivatives were tested for againstPregnenolone cancerous was cells: modified colon to (H aT-29, benzylidene HCT-15), oxime central and nervous two other. system The (SF-295), derivatives lungs were (HOP-62, tested forA- against cancerouscancerous cells:cells: coloncolon (HT-29, (HT-29, HCT-15), HCT-15), central central nervous nervous system system (SF-295), (SF-295), lungs lungs (HOP-62, (HOP-62, A-549) A- 549)against and cancerous breast (MCF-7). cells: colon All of(H T-29,the derivatives HCT-15), centralshowed nervous promising system anticancer (SF-295), properties lungs (HOP-62, [37]. The A- and549) breastand breast (MCF-7). (MCF-7). All of All the of derivatives the derivatives showed showed promising promising anticancer anticancer properties properties [37]. The [37]. oxime The presented in Figure 19 has a specific function as an inhibitor of kinases during the cell cycle and it also suppresses tumor growth. It was tested in liver cells (Hep G2) [38]. Symmetry 2020, 12, x FOR PEER REVIEW 10 of 17 Symmetry 2020, 12, x FOR PEER REVIEW 10 of 17 oximeSymmetry presented2020, 12, 575 in Figure 19 has a specific function as an inhibitor of kinases during the cell 10cycle of 17 oxime presented in Figure 19 has a specific function as an inhibitor of kinases during the cell cycle and it also suppresses tumor growth. It was tested in liver cells (Hep G2) [38]. andSymmetry it also 2020suppresses, 12, x FOR tumor PEER REVIEW growth. It was tested in liver cells (Hep G2) [38]. 10 of 17 oxime presented in Figure 19 has a specific function as an inhibitor of kinases during the cell cycle and it also suppresses tumor growth. It was tested in liver cells (Hep G2) [38].

FigureFigure 19. 19. Indirubin 3′oxime. Figure 19. IndirubinIndirubin 330′oxime.

OtherOther oximes oximes that that display anticancer activity are alkannin and shikoninshikonin derivatives.derivatives. These These Other oximes that display anticancerFigure 19.activity Indirubin are 3 ′alkanninoxime. and shikonin derivatives. These modifiedmodified compoundscompounds (Figure(Figure 20 20)) show show no no activity activity in healthy in healthy cells, butcells, they but are they active are in active K562 leukemiain K562 modified compounds (Figure 20) show no activity in healthy cells, but they are active in K562 leukemiacells [39]. cells [39]. leukemiaOther cells oximes[39]. that display anticancer activity are alkannin and shikonin derivatives. These modified compounds (Figure 20) show no activity in healthy cells, but they are active in K562 HO HO leukemia cells [39].HO N OMe HO N OMe N OMe N OMe HO HO N OMe N OMe

N OMe O N OMe O HO N OMe O HO N OMe O HO HO N OMe OO N OMe O O HO (a)O HO (b) O (a) (b) O O Figure 20. (a) Shikonin(a) and (b) alkannin oxime derivatives. (b) Figure 20.20. (a) Shikonin and (b) alkannin oximeoxime derivatives.derivatives. Qin et al. prepared oximeFigure derivatives 20. (a) Shikonin of α and,β-unsaturated (b) alkannin oxime tetralone. derivatives. All synthetized compounds Qin etet al.al. prepared oximeoxime derivativesderivatives ofof αα,,ββ-unsaturated-unsaturated tetralone.tetralone. All synthetized compounds were tested on its antiproliferative activity on human cancer cells: PC-3, HT-29, MCF-7, H-460, A-549, werewere testedtestedQin oneton al. its prepared antiproliferative oxime derivatives activityactivity onon of human α,β-unsaturated cancer cells: tetralone. PC-3, HT-29,All synthetized MCF-7, H-460, compounds A-549, PaCa-2 and PANC-1. The most active compounds were then assessed for their mechanistic effects on PaCa-2were and tested PANC-1. on its antiproliferative The most active activity compounds on human were cancer then cells: assessed PC-3, for HT-29, their MCF-7, mechanistic H-460, eeffectsff A-549,ects on the EGF receptor (EGFR) tyrosine kinase (TK), BRAFV600E gene mutation and tubulin polymerization. thethe PaCa-2 EGFEGF receptorreceptor and PANC-1. (EGFR)(EGFR) The tyrosinetyrosine most active kinasekinase compounds (TK),(TK), BRAFBRAF wereV600EV600E then genegene assessed mutation mutation for and andtheir tubulin tubulin mechanistic polymerization. polymerization. effects on In vitro studies were carried out in order to determine the potential of reversion of the efflux- InIn vitrovitrothe EGFstudies studies receptor were were (EGFR) carried carried tyrosine out out in order inkinase order to (TK), determine to BRAFdetermineV600E the potentialgene the mutationpotential of reversion and of tubulinreversion of the polymerization. effl ofux-mediated the efflux- mediated resistance of cancer cells. Three of the oxime derivatives (Figure 21) were extremely active. resistancemediatedIn vitro resistance of studies cancer were cells.of cancer carried Three cells. ofout the Three in oxime order of the derivatives to oximedetermine derivatives (Figure the potential 21 )(Figure were of extremely 21) reversion were extremely active. of the efflux- active. mediated resistance of cancer cells. Three of the oxime derivatives (Figure 21) were extremely active.

Figure 21. Oxime derivatives of α,β-unsaturated tetralone: (a) chlorinated, (b) brominated; and (c) Figure 21. Oxime derivatives of α,β-unsaturated tetralone: (a) chlorinated, (b) brominated; and (c) FigureFigure 21. OximeOxime derivatives derivativesdibrominated of of αα,β,β-unsaturated-unsaturated and multimethoxy tetralone: tetralone: (a)derivative. (a )chlorinated, chlorinated, (b) (b )brominated; brominated; and and (c) dibrominated and multimethoxy derivative. (c) dibrominated and multimethoxydibrominated derivative. and multimethoxy derivative. Significant antiproliferative activity was presented by one of the oxime compounds (Figure 21c) Significant antiproliferative activity was presented by one of the oxime compounds (Figure 21c) againstSignificant theSignificant PANC-1, antiproliferative antiproliferative A-549, PaCa-2 activity activity and wasPC-3 was presented presencell lines,ted byby achieving oneone of the IC oxime oxime50 value compounds compounds of 0.02 µM. (Figure (Figure Another 21c) 21 c) againstagainst the the PANC-1, PANC-1, A-549, A-549, PaCa-2 PaCa-2 and and PC-3 PC-3 cell cell lines,lines, achievingachieving ICIC5050 valuevalue ofof 0.02 0.02 µM. µM. Another Another compoundagainst the (Figure PANC-1, 21a) A-549, inhibited PaCa-2 the andBRAF PC-3V600E cellgene lines, mutation achieving with ICan50 ICvalue50 value of of 0.02 0.9µ µM.M. Another One of V600E compoundcompound (Figure (Figure 21a) 21a) inhibited inhibited the the BRAF BRAFV600EV600E gene gene mutationmutation with anan ICIC5050 valuevalue of of 0.9 0.9 µM. µM. One One of of thecompound oxime analogs (Figure (Figure 21a) inhibited 21c) presented the BRAF excellentgene inhibitory mutation activity with anto ICEGFR50 value TK (IC of 0.950 ofµ 0.07M. One µM). of the theoxime oxime analogs analogs (Figure (Figure 21c) 21c) presented presented excelle excellentnt inhibitoryinhibitory activity toto EGFREGFR TK TK (IC (IC5050 of of 0.07 0.07 µM). µM). Moreover,the oxime all analogs three compounds (Figure 21c) have presented been indicated excellent inhibitoryto have dual activity roles as to anticancer EGFR TK (ICagents50 of and 0.07 MDRµM). Moreover,Moreover, all allthree three compounds compounds have have been been indicated indicated to to havehave dualdual roles asas anticancer anticancer agents agents and and MDR MDR (multidrugMoreover, allresistance) three compounds reversal agents have been [40].indicated Additionally, to have Koz dualłowska roles et asal. anticancer evaluated agentsthe cytotoxicity and MDR (multidrug(multidrug resistance) resistance) reversal reversal agents agents [40]. [40]. Additionally, Additionally, KozKozłowska etet al.al. evaluatedevaluated the the cytotoxicity cytotoxicity of(multidrug naringenin resistance) derivatives reversal in the agentshuman [40 colon]. Additionally, adenocarcinoma Kozłowska HT-29 et cell al. line. evaluated The incorporation the cytotoxicity of of naringeninof naringenin derivatives derivatives in in the the human human colon colon aden adenocarcinomaocarcinoma HT-29 cellcell line.line. The The incorporation incorporation of of theof naringeninoxime group derivatives into one inof thethe humancompounds colon allowe adenocarcinomad this compound HT-29 cellto become line. The a highly incorporation potent the theoxime oxime group group into into one one of of the the compounds compounds alloweallowedd thisthis compound toto becomebecome a a highly highly potent potent antiproliferativeof the oxime group agent into from one a ofnonactive the compounds substrate. allowed The oxime this compound(Figure 10b) to had become an IC a50 highly = 4.59 potent± 0.56 antiproliferativeantiproliferative agent agent from from a anonactive nonactive substrate. substrate. TheThe oximeoxime (Figure 10b)10b) hadhad an an IC IC5050 = =4.59 4.59 ± ±0.56 0.56 µg/mL.antiproliferative Further, three agent other from oximes a nonactive revealed substrate. decreased The IC50 oxime value (Figure compared 10b) to had the anpositive IC50 =control,4.59 µg/mL.µg/mL. Further, Further, three three other other oximes oximes revealed revealed decreased decreased ICIC5050 valuevalue comparedcompared to to the the positive positive control, control, ± 0.56 µg/mL. Further, three other oximes revealed decreased IC50 value compared to the positive control,

Symmetry 2020, 12, 575 11 of 17 Symmetry 2020, 12, x FOR PEER REVIEW 11 of 17 cisplatincisplatin and were and were a bit weakera bit weaker than thethan cytostatic the cytostatic antibiotic, antibiotic, doxorubicin doxorubicin [23]. Zha[23]. etZha al. et synthesized al. synthesized α β , -unsaturatedα,β-unsaturated carbonyl-based carbonyl-based oximes oximes containing containing ligustrazine ligustrazine moiety. moiety. Those Those compounds compounds strongly strongly inhibitedinhibited growth growth of five of cancer five cancer cell types, cell types, A-549, A-549, PC-3, MCF-7,PC-3, MCF-7, PaCa-2 PaCa-2 and HT-29. and HT-29. The best The activity, best activity, as V600E an inhibitoras an inhibitor of tubulin of tubulin polymerization, polymerization, BRAF BRAF, focalV600E, adhesionfocal adhesion kinase kinase (FAK) (FAK) and EGFR-TK, and EGFR-TK, was was displayeddisplayed by the by oxime the oxime shown shown in Figure in Figure 22[41 22]. [41].

Figure 22. α,β-unsaturated carbonyl based oxime with ligustrazine moiety.

Often, oximesFigure are more 22. α polar,β-unsaturated than their baselinecarbonyl molecules based oxime [42 ].with Griseofulvin ligustrazine oxime moiety. derivatives proved to have improved anticancer activity than the baseline molecule. Presence of the oxime moiety Often, oximes are more polar than their baseline molecules [42]. Griseofulvin oxime derivatives at the 40 position improved the potency 2-fold to 12 µM[43]. proved to have improved anticancer activity than the baseline molecule. Presence of the oxime 6. A Counteractivemoiety at the 4 Agent′ position to Organophosphorusimproved the potency Compound 2-fold to 12 Poisoning µM [43].

Poisoning6. A counteractive from organophosphorus Agent to Organophosphorus (OP) compounds Compound is a very large Poisoning therapeutic problem, especially from pesticides and substances that pose serious danger to the nervous system. Treating of OP-poisoning depends onPoisoning the type from of nerve organophosphorus agent, which can(OP) distinguish compounds the is G-type a very and large V-type therapeutic according problem, to volatilityespecially [44]. Additionallyfrom pesticides it is and proven substances that the that location pose ofserious the oxime danger moiety to the is nervous the most system. important Treating for theof capacityOP-poisoning of reversing depends diff onerent the OP type inhibitors of nerve e ffagectent, [45 which]. There can are distinguish two therapeutic the G-type agents and used V-type in OPaccording poisoning: to volatility pralidoxime [44]. andAdditionally obidoxime it is (Figure proven 23 thata,b), the which location are of applied the oxime as reactivators moiety is the of most OP-inhibitedimportant acetylcholinesterase for the capacity of reversing (AChE) in different the presence OP inhibitors of reversible effect antagonists [45]. There of are a muscarinictwo therapeutic receptor,agents such used as, forin example,OP poisoning: atropine pralidoxime [44]. Recently, and pralidoxime obidoxime was (Figure tested 23a,b),in vivo whichfor its tissueare applied and as bloodreactivators distribution of profiles OP-inhibited in nonintoxicated acetylcholinesterase rats. The considerable (AChE) in the uptake presence was observedof reversible in the antagonists kidney of and quitea muscarinic lower rates receptor, were observed such as, infor the example, liver, lung atropine and heart, [44]. withRecently, lesser pralidoxime amounts in was the braintested and in vivo bloodfor [46 its]. Anothertissue and three blood promising distribution oxime profiles drugs in are nonintoxicated asoxime dichloride, rats. The trimedoxime considerable dibromide uptake was and methoximedichloride,observed in the kidney which and quite were synthesizedlower rates were in the observed previous in century the liver, [44 ].lung Wilhelm and heart, et al. testedwith lesser reactivatorsamounts on in OP-poisoned the brain and guinea blood pigs. [46]. Methoximedichloride Another three promising is effi oximecacious drugs against are broad asoxime spectrum dichloride, of OPtrimedoxime (soman, tabun, dibromide cyclosarin, and sarinmethoximedichloride, and VX, and the chlorpyrifoswhich were oxon,synthesized pesticides in the paraoxon previous and century phorate[44]. oxon) Wilhelm in case et of al. 24-h tested survivability reactivators in equimolar on OP-poisoned dose (146 µguineamol/kg). pigs. Asoxime Methoximedichloride dichloride was is also activeefficacious but onagainst the second broad tier, spectrum trimedoxime of OP dibromide (soman, astabun, the toxiccyclosarin, compound sarin was and tested VX, inand a the dosechlorpyrifos of 35 µmol/kg oxon, and opesticidesffered survival paraoxon protection and phorate between oxon) the secondin case andof 24-h third survivability tier [47]. Costa in equimolar et al. proposeddose two(146 new µmol/kg). oximes (FigureAsoxime 23 c,d)dichloride to reactivate was humanalso active AChE but and on butyrylcholinesterase the second tier, trimedoxime (BChE) that hasdibromide been inhibited as the toxic by organophosphate compound was tested compounds, in a dose mainly of 35 µmol/kg the inhibitory and offe activityred survival of three protection OPs: chlorpyrifos,between diazinonthe second and and malathion third tier [48 ].[47]. Unfortunately, Costa et al. oximesproposed are two mostly new useless oximes against (Figure soman 23c,d) to poisoningreactivate [49]. human AChE and butyrylcholinesterase (BChE) that has been inhibited by organophosphate compounds, mainly the inhibitory activity of three OPs: chlorpyrifos, diazinon and malathion [48]. Unfortunately, oximes are mostly useless against soman poisoning [49].

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FigureFigure 23.23.23.( a) Pralidoxime;(a()a ) Pralidoxime;Pralidoxime; (b) obidoxime; (b(b) ()c )(obidoxime;Eobidoxime;)-2-((E)-3-(hydroxyimino)butan-2-ylidene)hydrazinecarboth (c()c ) (E(E)-2-(()-2-((EE)-3-(hydroxyimino)butan-2-)-3-(hydroxyimino)butan-2- ylidene)hydrazinecarbothioamideylidene)hydrazinecarbothioamideioamide and (d) (2E,3E)-3-(2-phenylhydrazono)butan-2-one and and (d (d) (2) (2EE,3,3EE)-3-(2-phenylhydrazono)butan-2-one)-3-(2-phenylhydrazono)butan-2-one oxime. oxime. oxime.

The oxime presented inin FigureFigure 23 23cc reached reached a a percent percent (%) (%) reactivation reactivation ±SEM SEM at at a concentrationa concentration of The oxime presented in Figure 23c reached a percent (%) reactivation± ± SEM at a concentration of1 µ 1M µM of of 10 10 0.016,± 0.016, and and in in Figure Figure 23 23dd showed showed a a value value of of 7 7 ±0.009 0.009 againstagainst chlorpyrifos.chlorpyrifos. The oxime of 1 µM of 10± ± 0.016, and in Figure 23d showed a value of 7 ± 0.009 against chlorpyrifos. The oxime presented in Figure 2323bb had a percentpercent (%) reactivation ± SEM at a concentration of 1 µMµM of 20 ± 0.010,0.010, presented in Figure 23b had a percent (%) reactivation ±± SEM at a concentration of 1 µM of 20 ± ±0.010, and shown in Figure 23b23b oxime 2 showed a value of 12 ± 0.0250.025 against against the the second second OP. OP. The oxime and shown in Figure 23b oxime 2 showed a value of 12 ± ±0.025 against the second OP. The oxime presented inin FigureFigure 23 23dd had had percent percent (%) (%) reactivation reactivation SEM± SEM at aat concentration a concentration of 1ofµ M1 µM of 5 of 0.012,5 ± 0.012, and presented in Figure 23d had percent (%) reactivation± ± SEM at a concentration of 1 µM of± 5 ± 0.012, andthe oximethe oxime shown shown in Figure in Figure 23d showed 23d showed a value a ofvalue 12 of0.019 12 ± against 0.019 against the third the OP. third The oximesOP. The shown oximes in and the oxime shown in Figure 23d showed a value ±of 12 ± 0.019 against the third OP. The oximes shownshownFigure in 23in Figurec,d Figure had 23c,d 23c,d similar had had activity similar similar to activity pralidoxime:activity to to pralidoxime: pralidoxime: oxime (Figure oxime oxime 23 (Figurec) (Figure had the 23c) 23c) same had had percent the the same same reactivation percent percent reactivationreactivationagainst diazinon against against poisoning diazinon diazinon as poisoning poisoning obidoxime as as [ 48obidoxime obidoxime]. Žunec et[48]. [48]. al. presentedŽunec Žunec et et theiral. al. presented presentedin vivo research their their in in on vivo vivo new researchresearchtherapeutic on on new agentsnew therapeutic therapeutic against paraoxon agents agents against against poisoning. paraoxon paraoxon Two oximespoisoning. poisoning. presented Two Two oximes oximes in Figure presented presented 24, stood in in outFigure Figure for their24, 24, stoodstoodlow acuteout out for for toxicities their their low low and acute acute excellent toxicities toxicities antidotal and and excellent excellent effects. antidotal antidotal effects. effects.

Figure 24. Bispyridinium oxime derivatives: with propyl linker (a) and butyl linker (b). Figure 24. Bispyridinium oxime derivatives: with propyl linker (a) and butyl linker (b) OximesFigure have 24. beenBispyridinium applied oxime in male derivatives: mice in thewith amount propyl linker of 5% (a) of and their butyl lethal linker dose (b) (LD50) and combined with atropine, resulting in a protection index (PI) of 74.1 and 100, respectively. Moreover, the Oximes have been applied in male mice in the amount of 5% of their lethal dose (LD50) and useOximes of these combinationshave been applied increased in male the survival mice in ofthe all amount animals upof 5% to 63.0 of their of the lethal LD50 ofdose paraoxon. (LD50) and Both combined with atropine, resulting in a protection index (PI) of 74.1 and 100, respectively. Moreover, combinedoximes might with beatropine, good antidotes resulting for in OP a protection poisoning. index Moreover, (PI) of both 74.1 monoximes and 100, respectively. are the least toxicMoreover, among the use of these combinations increased the survival of all animals up to 63.0 of the LD50 of paraoxon. theall use tested. of these The combinations LD50 of oxime increased presented the in Figuresurvival 24 aof was all animals 672.8 mg up/kg to [ 5063.0]. Kucaof the et LD al.50 presented of paraoxon. their Both oximes might be good antidotes for OP poisoning. Moreover, both monoximes are the least toxic Bothresearch oximes results might on be trisquarternary good antidotes bisoxime for OP poison as a potentialing. Moreover, drug against both OPmonoximes poisoning. are Unfortunately, the least toxic it among all tested. The LD50 of oxime presented in Figure 24a was 672.8 mg/kg [50]. Kuca et al. amongcannot all be consideredtested. The anLD AChE50 of oxime reactivator presented because in the Figure rate of24a reactivation was 672.8 of mg/kg AChE was[50]. worse Kuca thanet al. for presented their research results on trisquarternary bisoxime as a potential drug against OP poisoning. presentedstandard their reactivators. research The results oxime on trisquarternary shown in Figure bisoxime 25 has indicated as a pote tontial reactivate drug against AChE OP after poisoning. inhibition Unfortunately, it cannot be considered an AChE reactivator because the rate of reactivation of AChE Unfortunately,by sarin and agent it cannot VX with be consider a percented reactivation an AChE reactivator above 20% because at high concentrationsthe rate of reactivation (10-3 M). of Moreover, AChE was worse than for standard reactivators. The oxime shown in Figure 25 has indicated to reactivate wasthis worse compound than for will standard not penetrate reactivators. the blood–brain The oxime barrier shown due in toFigure three 25 positive has indicated charges. to However, reactivate the AChE after inhibition by sarin and agent VX with a percent reactivation above 20% at high AChEhigh hydrophilicityafter inhibition and by relatively sarin and large agent size ofVX the with studied a percent bisoxime reactivation reactivator makesabove it20% an interestingat high concentrations (10-3 M). Moreover, this compound will not penetrate the blood–brain barrier due to concentrationscandidate for BChE(10-3 M). pseudocatalytic Moreover, this reactivation compound [51 will]. not penetrate the blood–brain barrier due to threethree positive positive charges. charges. However, However, the the high high hydroph hydrophilicityilicity and and relatively relatively large large size size of of the the studied studied bisoximebisoxime reactivator reactivator makes makes it it an an interesting interesting cand candidateidate for for BChE BChE pseudocatalytic pseudocatalytic reactivation reactivation [51]. [51].

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Figure 25. (E)-1,1’-((Methylsulfoniodiyl)bis(ethane-2,1-diyl))bis(4-((E)- (hydroxyimino)methyl)pyridin-1-ium). Figure 25. (E)-1,1’-((Methylsulfoniodiyl)bis(ethane-2,1-diyl))bis(4-((E)- Figure 25. (E)-1,10-((Methylsulfoniodiyl)bis(ethane-2,1-diyl))bis(4-((E)-(hydroxyimino)methyl)pyridin-1-ium). (hydroxyimino)methyl)pyridin-1-ium).AnotherFigure 25.approach (E)-1,1’-((Methylsulfoniodiyl)bi was presented s(ethane-2,1-diyl))bis(4-((by Santoni and Ecolleagues.)- They synthesized a tetrahydroacridineAnother(hydroxyimino)methyl)pyridin-1-ium). approach linked was presentedto the non-quaternary by Santoni and oxime colleagues. reactivator They synthesized presented ain tetrahydroacridine Figure 26 and a Another approach was presented by Santoni and colleagues. They synthesized a linkedchlorinated to the derivative. non-quaternary Both molecules oxime reactivator proved to presented have excellent in Figure nerve 26 and agent a chlorinated antidote efficacy derivative. (kr2 tetrahydroacridineAnother approachlinked to wasthe non-quaternarypresented by Sant oximeoni reactivatorand colleagues. presented They insynthesized Figure 26 anda a Bothreactivation), molecules better proved than to the have well-known excellent nerve drug agent obidoxime antidote against efficacy three (kr2 OP reactivation),s: agent VX, better sarin thanand chlorinatedtetrahydroacridine derivative. linked Both moleculesto the non-quaternary proved to haoximeve excellent reactivator nerve presented agent in antidote Figure 26efficacy and a (kr2 theparaoxon well-known [52]. drug obidoxime against three OPs: agent VX, sarin and paraoxon [52]. reactivation),chlorinated better derivative. than theBoth well-known molecules proved drug toobidoxime have excellent against nerve three agent OP antidotes: agent efficacy VX, sarin (kr2 and reactivation), better than the well-known drug obidoxime against three OPs: agent VX, sarin and paraoxon [52]. paraoxon [52].

Figure 26. Tetrahydroacridine based oxime. Figure 26. Tetrahydroacridine based oxime. Figure 26. Tetrahydroacridine based oxime. Zorbaz et al. presented presented two two oximes oximes (Figure (Figure 27a,b27a,b)) that proved to have notable potential in cyclosarinZorbaz poisoning et al. especiallypresented two in reversingreversingoximes (Figure hBChEhBChE 27a,b blockage.blockage.) that proved Moreover, Moreover, to have bothnotable oximes potential have in been Zorbazcyclosarin et poisoningal. presented especially two inoximes reversing (Figure hBChE 27a,b blockage.) that provedMoreover, to bothhave oximes notable have potential been in predicted toto crosscross thethe blood-brainblood-brain barrierbarrier atat satisfactorysatisfactory levels.levels. [[53].53]. cyclosarinpredicted poisoning to cross theespecially blood-brain in reversingbarrier at satisfactory hBChE blockage. levels. [53]. Moreover, both oximes have been predicted to cross the blood-brain barrier at satisfactory levels. [53].

Figure 27. Hydroxypiridine oxime derivatives: with pentyl (a) and heptyl (b) linker FigureFigure 27.27. Hydroxypiridine oximeoxime derivatives:derivatives: with pentyl ((a)a) and heptyl ((b)b) linker.linker

An activeactiveAn Figureactive compoundcompound compound27. Hydroxypiridine able able able to to reverse to reverse reverse oxime OP OP poisoningOPderivatives: poisoningpoisoning was with was was presented pentyl presented presented (a) byand by Kovarik heptyl byKovarik Kovarik (b) et al.etlinker al. Theet The al. best bestThe results best results in the in vivo study were obtained against agent VX and paraoxon. The compound shown in inresults the in in vivo the studyin vivo were study obtained were obtained against agentagainst VX agent and paraoxon.VX and paraoxon. The compound The compound shown in shown Figure 28in AnFigure active 28 proved compound to have able the to greatest reverse antidotal OP poisoning potential was with presented a PI above by 10 Kovarikand ensured et al. mouse The best provedFigure 28 to haveproved the to greatest have the antidotal greatest potential antidotal with potential a PI above with 10 anda PI ensuredabove 10 mouse and survivalensured againstmouse resultssurvival in the inagainst vivo 10×study the were LD50 obtained. Moreover, agai thisnst oxime agent provedVX and to paraoxon. have a better The compoundPI against tabun shown in 10survivalthe LD against50. Moreover, 10× the this LD oxime50. Moreover, proved tothis have oxime a better proved PI against to have tabun a poisoningbetter PI against than the tabun other Figure× poisoning 28 proved than to the have other the commonly greatest known antidotal drug, potential trimedoxime with bromide. a PI above No significant 10 and ensuredcytotoxicity mouse commonlypoisoningwas observed than known the [54]. drug,other trimedoximecommonly known bromide. drug, No trimedoxime significant cytotoxicity bromide. No was significant observed cytotoxicity [54]. survival against 10× the LD50. Moreover, this oxime proved to have a better PI against tabun was observed [54]. poisoning than the other commonly known drug, trimedoxime bromide. No significant cytotoxicity was observed [54].

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Figure 28. Triazol oxime derivative. Figure 28. Triazol oxime derivative. 7. Conclusions 7. ConclusionsIn conclusion, oximes were indicated to have a therapeutic potential. Some have already been used as drugsIn conclusion, for OP poisoning oximes andwere antibiotics. indicated to Many have newly a therapeutic synthesized potential. oximes Some have have shown already promising been usedproperties, as drugs such for as antimicrobial,OP poisoning anti-inflammatory, and antibiotics. antioxidant,Many newly anticancer synthesized and againstoximes OPhave poisoning. shown promisingConsequently, properties, further such studies as antimicrobial, on oximes and anti their-inflammatory, biological activitiesantioxidant, should anticancer be undertaken and against to OPdetermine poisoning. more Consequently, active agents thatfurther might studies be considered on oximes as eandffective their drugs. biological activities should be undertaken to determine more active agents that might be considered as effective drugs. Funding: This work was supported by the project: “Synthesis of new fragrances from raw materials of Funding:a natural This origin work with was applications supported by in the perfumery, project: “Synthesis cosmetics of andnew householdfragrances from chemistry” raw materials (SYNFRA; of a natural LIDER Program, LIDER/4/0099/L-7/15/NCBR/2016), which was financed by the National Centre for Research origin with applications in perfumery, cosmetics and household chemistry” (SYNFRA; LIDER Program, and Development—Poland. LIDER/4/0099/L-7/15/NCBR/2016), which was financed by the National Centre for Research and Development— Poland.Conflicts of Interest: On behalf of all authors, the corresponding author states that there is no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of the data; in the Conflictswriting of of the Interest: manuscript, On behalf or in of the all decision authors, to the publish corresponding the results. author states that there is no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of the data; in the writingReferences of the manuscript, or in the decision to publish the results.

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