molecules

Review Peroxides with , , Fungicidal and Antiviral Bioactivity: Properties, Synthesis and Reactions

Vera A. Vil’ 1,2,3, Ivan A. Yaremenko 1,2,3, Alexey I. Ilovaisky 1 and Alexander O. Terent’ev 1,2,3,* ID

1 N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prospekt, 119991 Moscow, Russia; [email protected] (V.A.V.); [email protected] (I.A.Y.); [email protected] (A.I.I.) 2 Faculty of Chemical and Pharmaceutical Technology and Biomedical Products, D. I. Mendeleev University of Chemical Technology of Russia, 9 Miusskaya Square, 125047 Moscow, Russia 3 All-Russian Research Institute for Phytopathology, B. Vyazyomy, 143050 Moscow, Russia * Correspondence: [email protected]; Tel.: +7-916-385-4080

Received: 9 October 2017; Accepted: 30 October 2017; Published: 2 November 2017

Abstract: The biological activity of organic peroxides is usually associated with the antimalarial properties of and its derivatives. However, the analysis of published data indicates that organic peroxides exhibit a variety of biological activity, which is still being given insufficient attention. In the present review, we deal with natural, semi-synthetic and synthetic peroxides exhibiting anthelmintic, antiprotozoal, fungicidal, antiviral and other activities that have not been described in detail earlier. The review is mainly concerned with the development of methods for the synthesis of biologically active natural peroxides, as well as its isolation from natural sources and the modification of natural peroxides. In addition, much attention is paid to the substantially cheaper biologically active synthetic peroxides. The present review summarizes 217 publications mainly from 2000 onwards.

Keywords: peroxides; anthelmintic; antiprotozoal; fungicidal; antiviral

1. Introduction Peroxides are widely used in various areas of life [1–3]. Traditional and the most developed field is the application of peroxides as radical initiators in industrial processes in the manufacture of polymers from unsaturated monomers: styrenes, butadienes, chlorovinyls, ethylenes, acrylates, as well as in crosslinking of silicone rubbers, acrylonitrile-butadiene rubbers, fluororubbers, polyethylene, ethylene-propylene copolymer, etc. [4–9]. Hydrogen peroxide and peracids are active components of antiseptics and disinfectants [10–14]. Synthesis and mechanism of antiseptic action of hydrogen peroxide and the most common peracids (performic, peracetic, etc.) are elucidated in a few studies [15–17] and are not considered in this review. Antimalarial properties of peroxides are currently intensively studied. Artemisinin (Qinghaosu) (1), a natural peroxide possessing high antimalarial activity, was isolated in 1971 from leaves of annual wormwood (Artemisia annua) in the context of the scientific program “Project 523”, initiated by Chinese government in 1967 [18–20]. The Nobel Prize in Physiology or Medicine 2015 was awarded to Chinese pharmaceutical chemist Tu Youyou “for her discoveries concerning a novel therapy against ” [21–23]. Considering the development of resistance of Plasmodium to some traditional , such as , , and mefloquine, and other anti-parasitic ones, pharmaceuticals based on artemisinin and its semi-synthetic derivatives— (2), (3) and (4) (Figure1)—are currently the most effective drugs against malaria [24–30].

Molecules 2017, 22, 1881; doi:10.3390/molecules22111881 www.mdpi.com/journal/molecules Molecules 2017, 22, 1881 2 of 39 Molecules 2017, 22, 1881 2 of 39

Molecules 2017, 22, 1881 2 of 39 H H H H O H O O O H H H O O O O OO OO OO OO HO H H H H O HO HO HOO O O O O O O O H H O O H H H H H O O H O OH O O O OH O O artemisininO (1) dihydroartemisininOH (2) artemetherO (3) artesunate (4) OH O 1 2 3 4 artemisinin ( ) FigureFiguredihydroartemisinin 1. 1.Artemisinin Artemisinin (andand) its artemether semi-synthetic ( )derivatives. derivatives.artesunate ( )

The modern trend Figurein medicinal 1. Artemisinin chemistry and its of semi-synthetic peroxides is derivatives. the search of effective anticancer The modern trend in medicinal chemistry of peroxides is the search of effective anticancer drugs. The natural and synthetic peroxides exhibiting a cytotoxic effect on cancer cells already drugs.The The modern natural trend and syntheticin medicinal peroxides chemistry exhibiting of peroxides a cytotoxic is the search effect of on effective cancer cellsanticancer already include hundreds of compounds [31–34]. Peroxides possessing antimalarial and cytotoxic activity includedrugs. hundreds The natural of compounds and synthetic [31 –peroxides34]. Peroxides exhibiti possessingng a cytotoxic antimalarial effect on and cancer cytotoxic cells activityalready are are the subject of numerous studies [35–42], and are not considered in this review. include hundreds of compounds [31–34]. Peroxides possessing antimalarial and cytotoxic activity the subjectIn the of numerouspresent review, studies we [deal35–42 with], and natural, are not semi-synthetic considered inand this synthetic review. peroxides exhibiting are the subject of numerous studies [35–42], and are not considered in this review. anthelmintic,In the present antiprotozoal, review, we fungicidal, deal with antiviral natural, and semi-synthetic other activities and that synthetic have not peroxides been described exhibiting in In the present review, we deal with natural, semi-synthetic and synthetic peroxides exhibiting anthelmintic,detail earlier. antiprotozoal, The review is fungicidal, mainly concerned antiviral with and the other synthesis activities of such that peroxides, have not beenas well described as its anthelmintic, antiprotozoal, fungicidal, antiviral and other activities that have not been described in in detailisolation earlier. from Thenatural review sources is mainly and covers concerned literature with published the synthesis between of 1912 such and peroxides, 2017. as well as its detail earlier. The review is mainly concerned with the synthesis of such peroxides, as well as its isolationThere from are natural several sources review and articles, covers literaturewhere the published various betweenkinds of 1912the andbiological 2017. activity of isolation from natural sources and covers literature published between 1912 and 2017. artemisininThere are [43–45] several and review artemether articles, [46,47]; where the theproblems various of kindstrematode of the biological therapy activity with of There are several review articles, where the various kinds of the biological activity of artemisininartemisinin, [43 its–45 derivatives] and artemether and several [46 synthetic,47]; the oz problemsonides [48]; of and trematode antiviral activity infection of therapyartemisinin with artemisinin [43–45] and artemether [46,47]; the problems of trematode infection therapy with artemisinin,and artesunate its derivatives [49] are anddiscussed. several Advances synthetic ozonidesin the development [48]; and antiviral of anti-parasitic activity of peroxides artemisinin are and artemisinin, its derivatives and several synthetic ozonides [48]; and antiviral activity of artemisinin artesunatedescribed [49 in] arethe discussed.review of AdvancesMuraleedharan in the [50]. development A number ofof anti-parasitic reviews are devoted peroxides to arepromising described and artesunate [49] are discussed. Advances in the development of anti-parasitic peroxides are anthelmintic peroxides [51]. Some natural antiviral peroxides are mentioned in the review [52]. in thedescribed review in of the Muraleedharan review of Muraleedharan [50]. A number [50]. ofA reviewsnumber areof reviews devoted are to devoted promising to anthelminticpromising However, none of these articles pay sufficient attention to the methods of peroxide synthesis. peroxidesanthelmintic [51]. Someperoxides natural [51]. antiviral Some natural peroxides antiviral are mentioned peroxides inare the mentioned review [ 52in]. the However, review none[52]. of Since peroxides with a related structure have different types of activity, the systematization of theseHowever, articles none pay sufficientof these articles attention pay tosufficient the methods attention of peroxideto the methods synthesis. of peroxide synthesis. this review is based on the structure of the peroxide fragment (Figure 2). The first sections consider SinceSince peroxides peroxides with with a a related related structurestructure have different types types of of activity, activity, the the systematization systematization of of the preparation of cyclic peroxides in order of increasing cycle and the number of oxygen atoms in it, thisthis review review is basedis based on on the the structure structure of ofthe the peroxideperoxide fragment (Figure (Figure 2).2). The The first first sections sections consider consider while the last section deals with peroxides of acyclic structure. The following abbreviations are used thethe preparation preparation of of cyclic cyclic peroxidesperoxides in in order order of ofincreasing increasing cycle cycle and andthe number the number of oxygen of oxygen atoms in atoms it, in describing the biological activity of peroxides: minimum inhibitory concentration (MIC), in it,while while the thelast lastsection section deals dealswith peroxides with peroxides of acyclic of structure. acyclic structure. The following The followingabbreviations abbreviations are used minimum lethal concentration (MLC), half maximal inhibitory concentration (IC50), concentration of arein used describing in describing the biological the biological activity activity of pero of peroxides:xides: minimum minimum inhibitory inhibitory concentration concentration (MIC), (MIC), inhibiting 90% of activity (IC90), half maximal effective concentration (ЕС50), and median effective minimum lethal concentration (MLC), half maximal inhibitory concentration (IC50), concentration of minimumdose (ED lethal50) [53,54]. concentration (MLC), half maximal inhibitory concentration (IC50), concentration of inhibiting 90% of activity (IC90), half maximal effective concentration (ЕС50), and median effective inhibiting 90% of activity (IC90), half maximal effective concentration (EC50), and median effective dose (ED50) [53,54]. dose (ED50)[53,54].

Figure 2. Reviewed cyclic and acyclic peroxides.

2. 1,2-Dioxolanes FigureFigure 2. 2.Reviewed Reviewed cyclic and and acyclic acyclic peroxides. peroxides.

2. 1,2-Dioxolanes2. 1,2-DioxolanesA number of cyclic peroxides, many of which exhibit antibacterial, and anti-cancer activity, were isolated from the marine organisms, in particular from the sponges Plakinidae [55]. A number of cyclic peroxides, many of which exhibit antibacterial, antifungal and anti-cancer PlakinicA number acid of А cyclic (5) effectively peroxides, inhibits many of the which growth exhibit of fungi antibacterial, Saccharomyces antifungal cerevisiae and anti-cancerand Penicillium activity, wereactivity, isolated were from isolated the marine from organisms,the marine organisms, in particular in fromparticular the sponges from thePlakinidae sponges [55Plakinidae]. Plakinic [55]. acid A(Plakinic5 ) effectively acid inhibitsА (5) effectively the growth inhibits of fungi the Saccharomycesgrowth of fungi cerevisiae Saccharomycesand Penicillium cerevisiae atrounenetumand Penicillium[56 ];

Molecules 2017, 22, 1881 3 of 39 Molecules 2017, 22, 1881 3 of 39 plakinicatrounenetum acid F[56]; (7) andplakinicepi-plakinic acid F acid(7) and F (8) epi exhibit-plakinic moderate acid F antifungal (8) exhibit activity moderate against antifungalCandida albicansactivity andagainstAspergillus Candida fumigatusalbicans and[57 Aspergillus]; 1,2-dioxolane fumigatus acids [57];9 and 1,2-dioxolane10 inhibit acids the growth 9 and 10 of Candidainhibit the albicans growth[58 of]; andCandida plakortide albicans E[58]; (11 and) show plakortide good activity Е (11) show against goodTrypanosoma activity against brucei Trypanosoma(Scheme1)[ 59brucei]. (Scheme 1) [59].

Scheme 1. Antifungal and anti-parasitic activity of 1,2-dioxolanes, isolated from the sponges Plakinidae.

The firstfirst synthesissynthesis of diastereomericdiastereomeric saturated analogs of plakinic acids A, C and D 17 waswas reported in 19961996 byby BloodworthBloodworth andand colleaguescolleagues [[60].60]. Peroxides 17 were prepared in four steps from ketones 1212.. In In the the first first step, step, ketone ketone12 was 12 condensed was condensed with ethyl with 3-methylbut-2-enoate ethyl 3-methylbut-2-enoate with formation with cyclicformation lactones cyclic13 lactoneshydrolysis, 13 hydrolysis, which led towhich acids led14. to Peroxymercuration acids 14. Peroxymercuration of esters 15 followedof esters by15 reductionfollowed by with reduction sodium with borohydride sodium borohydride afforded 1,2-dioxolanes afforded 1,2-dioxolanes16 saponification, 16 saponification, which resulted which in 1,2-dioxolanesresulted in 1,2-dioxolanes17 with carboxylic 17 with group carboxylic (Scheme group2). (Scheme 2). The synthesissynthesis of diastereomericof diastereomeric 1,2-dioxolanes 1,2-dioxolanes22 from alkynes22 from was describedalkynes [was61]. Carboaluminationdescribed [61]. ofCarboalumination alkyne 18, followed of byalkyne treatment 18, followed of the intermediate by treatment alkenylaluminum of the intermediate with acetaldehyde,alkenylaluminum resulted with in acetaldehyde, resulted in an allylic alcohol that was oxidized to enone 19. Conjugate addition of an allylic alcohol that was oxidized to enone 19. Conjugate addition of H2O2 to 19 in the presence of LiOH followedH2O2 to 19 by acid-catalyzedin the presence esterification of LiOH followed of diastereomeric by acid-catalyzed dioxinole esterification by 2-methoxyethanol of diastereomeric provided alkoxydioxolanedioxinole by 2-methoxyethanol20. Substitution provided of the methoxyethoxy alkoxydioxolane group 20 in. 20Substitutionby the action of the of silyl methoxyethoxy keteneacetal group in 20 by the action of silyl keteneacetal ethyl thioacetal in the presence of TiCl4 led to thioether ethyl thioacetal in the presence of TiCl4 led to thioether 21 as a 1:1 mixture of two diastereomers. The21 as hardly-separable a 1:1 mixturecis of- andtwotrans diastereomers.-diastereomeric The peroxides hardly-separable22 were obtained cis- and as atrans result-diastereomeric of hydrolysis withperoxides high yield22 were (Scheme obtained3). as a result of hydrolysis with high yield (Scheme 3).

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Scheme 2. The first synthesis of saturated analogs of plakinic acids 17. Scheme 2. TheThe first first synthesis of saturated analogs of plakinic acids 17.

Scheme 3. The synthesis of diastereomeric analogs of plakinic acids 22. Scheme 3. The synthesis of diastereomeric analogs of plakinic acids 22.

In 2006,2006, thethe first first asymmetric asymmetric synthesis synthesis of of plakinic plakinic acids acids was was reported reported [62]. [62]. The keyThe stepkey ofstep side of chain side In 2006, the first asymmetric synthesis of plakinic acids was reported [62]. The key step of side chainconstruction construction was synthesis was synthesis of diastereomeric of diastereomeric allylic alcohols allylic25 fromalcohols bromobenzene. 25 from bromobenzene. This transformation This chain construction was synthesis of diastereomeric allylic alcohols 25 from bromobenzene. This transformationincluded subsequent included addition subsequent Mg-organic addition compound Mg-organic to crotonaldehyde compound with to formationcrotonaldehyde of alcohol with23, transformation included subsequent addition Mg-organic compound to crotonaldehyde with formationClaisen homologation of alcohol 23 resulted, Claisen in homologation ester 24, and reactionresulted ofin anester intermediate 24, and reaction aldehyde of an with intermediate propenyl formation of alcohol 23, Claisen homologation resulted in ester 24, and reaction of an intermediate aldehydelithium (Scheme with propenyl4). lithium (Scheme 4). aldehyde with propenyl lithium (Scheme 4). As a result of following transformationtransformation epoxy alcohol 29a was prepared, which was oxidized As a result of following transformation epoxy alcohol 29a was prepared, which was oxidized into aldehyde; subsequent addition of methylmagnesium bromide bromide resulted in isomeric secondary into aldehyde; subsequent addition of methylmagnesium bromide resulted in isomeric secondary epoxy alcohols 3030aа and 30b (Scheme(Scheme5 5).). AfterAfter transformationtransformation ofof minorminor 30b into 30a, the latter was epoxy alcohols 30а and 30b (Scheme 5). After transformation of minor 30b into 30a, the latter was reduced to diol 31. The The treatment treatment of of diol diol 3131 withwith stoichiometric quanti quantityty of of TsCl TsCl and excess of reduced to diol 31. The treatment of diol 31 with stoichiometric quantity of TsCl and excess of t-BuOK led to oxetaneoxetane 32.. The The ring ring opening opening with TMSOTf provided easily separable 3-hydroxy t-BuOK led to oxetane 32. The ring opening with TMSOTf provided easily separable 3-hydroxy hydroperoxides 33 and epi-33; 33 was converted into peroxy ketone 34 by subsequent silylation and hydroperoxides 33 and epi-33; 33 was converted into peroxy ketone 34 by subsequent silylation and oxidation. The The ketone ketone 3434 waswas transformed into into alkoxydioxolane alkoxydioxolane 3535,, and and after after that that into into thioester thioester 3636.. oxidation. The ketone 34 was transformed into alkoxydioxolane 35, and after that into thioester 36. The desirable plakinic acids 38 were prepared by hydrolysis of methyl esters 37. A similar strategy The desirable plakinic acids 38 were prepared by hydrolysis of methyl esters 37. A similar strategy was used for the synthesis of stereomeric acids 3939 from 3-hydroxy hydroperoxide epiepi-3333. was used for the synthesis of stereomeric acidsacids 39 fromfrom 3-hydroxy3-hydroxy hydroperoxidehydroperoxide epi--33.. A total synthesis of plakortide E (11) based on radical oxygenation of vinylcyclopropanes was A total synthesis of plakortide E (11) based on radicalradical oxygenationoxygenation of vinylcyclopropanesvinylcyclopropanes was reported [63,64]. The key intermediate 2-ethyl-1,1,2-cyclopropanetricarboxylate (42) prepared from reported [63,64]. [63,64]. TheThe key key intermediate intermediate 2-ethyl-1,1,2-cyclopropanetricarboxylate 2-ethyl-1,1,2-cyclopropanetricarboxylate ( 42) prepared prepared from methylene malonate 40(40) andα α-chloro ester41 41 was transformed into lactone43 43. The treatment of the methylene malonatemalonate ( (40)) and and -chloroα-chloro ester ester 41was was transformed transformed into into lactone lactone. The 43. treatmentThe treatment of the of latter the withlatteroxygen, with oxygen, Ph2Se2 Phand2Se AIBN2 andfurnished AIBN furnished spiro 1,2-dioxolane spiro 1,2-dioxolane44, followed 44, byfollowed lactone by ring lactone opening ring of latter with oxygen, Ph2Se2 and AIBN furnished spiro 1,2-dioxolane 44, followed by lactone ring opening44 of 44 to45 form diol 45. The precursor of the49 plakortide E 49 was synthesized from the openingto form of diol44 to .form The precursordiol 45. The of theprecursor plakortide of the E plakortidewas synthesized E 49 was from synthesized the iodo-derivative from the iodo-derivative of47 1,2-dioxolane 47 and the halogen48 derivative 48 by Negishi reaction. Desilylation49 iodo-derivativeof 1,2-dioxolane of 1,2-dioxolaneand the halogen 47 and derivative the halogenby derivative Negishi reaction.48 by Negishi Desilylation reaction. of Desilylation alcohol , of alcohol 49, subsequent oxidation and Horner–Wadsworth–Emmons olefination provided51 ester 51 ofsubsequent alcohol 49 oxidation, subsequent and oxidation Horner-Wadsworth-Emmons and Horner–Wadsworth–Emmons olefination provided olefination ester providedwhich ester was 51 which was hydrolyzed with formation of plakortide11 E (11) (Scheme 6) [63]. whichhydrolyzed was hydrolyzed with formation with of formation plakortide of Eplakortide ( ) (Scheme E (116)[) (Scheme63]. 6) [63].

Molecules 2017, 22, 1881 5 of 39 Molecules 2017, 22, 1881 5 of 39 Molecules 2017, 22, 1881 5 of 39 O Mg, CH CH=CHCHO OH (EtO) CCH PhBr 3 3 3 OH O Mg, CH93%3CH=CHCHO Ph (EtO)CH3CH3CCH2COOH3 Ph OEt PhBr o 93% Ph 23 CH3CH1402COOHC Ph 24 OEt 23 14085%oC 24 85% OH R2 OH R2 1) LiAlH4 OH R OH R 2)1) DMSO, LiAlH (COCl)2, Et3N 2 2 4 Ph R1 Ph R1 3)2) DMSO,Br (COCl)t-BuLi,2, EtTHF3N Ph R1 Ph R1 3) Br 25a R1 = CH3, R2 = H 25b R1 = CH3, R2 = H 79%t-BuLi, THF 25c25a R1 = CHH, 3,R2R=2 =CH H3 25b25d R R1 1= =CH H,3, RR22== CHH 3 79% 25c R1 = H, R2 = CH3 25d R1 = H, R2 = CH3

(EtO)3CCH3 1) LiAlH 25a (EtO)3CCH3 O 4 CH3CH2COOH 1) LiAlH 25a o O 2) DMSO,4 (COCl)2, Et3N CH1403CH2CCOOH o 2) DMSO, (COCl)2, Et3N 140 C Ph OEt 3) Zn, CBr4, PPh3 Ph OEt (EtO)3CCH3 26 3)4) Zn, n-BuLi CBr4, PPh3 25d (EtO)3CCH3 4) n-BuLi 25d CH CH COOH 26 76% 3 2 76% CH1403CHo2CCOOH 140oC OH OH 1) Me3Al, Cp2ZrCl2 Ph 1) Me3Al, Cp2ZrCl2 Ph Ph 2) n-BuLi, (CH O)n Ph 2) n-BuLi, (CH 2O)n 27 77% 2 28 27 77% 28 OH OH OH OOH Ti(OiPr)4, (-)-DET O O Ti(OiPr)4, (-)-DET O t-BuOOHt-BuOOH PhPh PhPh 93% 93% 29a 29b29b >80% ee SchemeScheme 4. 4. Construction Construction of asymmetric plakinic plakinic acids acidsacids side sideside chain. chain.chain.

SchemeScheme 5.5.Asymmetric Asymmetric synthesis of of plakinic plakinic acids acids 3838 andand 3939. . Scheme 5. Asymmetric synthesis of plakinic acids 38 and 39.

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SchemeScheme 6.6. Synthesis ofof plakortideplakortide EE ((1111)) byby radicalradical oxygenationoxygenation ofof cyclopropanes.cyclopropanes.

A similar strategy based on the radical oxygenation of vinyl cyclopropanes was used for the A similar strategy based on the radical oxygenation of vinyl cyclopropanes was used for the synthesis of synthesis of epiplakinic acid F (8) [65]. The vinyl cyclopropane 53 obtained from epiplakinic acid F (8)[65]. The vinyl cyclopropane 53 obtained from trans-1,2-cyclopropanedicarboxylate 52, trans-1,2-cyclopropanedicarboxylate 52, was then converted to 1,2-dioxolane 55 (Scheme 7). After was then converted to 1,2-dioxolane 55 (Scheme7). After separation of the diastereomeric mixture isomer 55b separation of the diastereomeric mixture isomer 55b was used for further transformations. was used for further transformations. Enantiomerically pure 55b was reduced by LiBH4 to alcohol 56, which was transformed to Enantiomerically pure 55b was reduced by LiBH to alcohol 56, which was transformed to vinylether 57 by subsequent PCC oxidation and Wittig4 olefination. Oxidation of 57 to methyl ester vinylether 57 by subsequent PCC oxidation and Wittig olefination. Oxidation of 57 to methyl ester 58, 58, reductive ozonolysis of 58, and Wittig olefination gave predominantly the Z-isomer of vinyl reductive ozonolysis of 58, and Wittig olefination gave predominantly the Z-isomer of vinyl iodide 59. iodide 59. The Negishi coupling of 59 with the halogen derivative led to the desired product 60. The Negishi coupling of 59 with the halogen derivative led to the desired product 60. Desilylation of 60 Desilylation of 60 followed by reduction of 61 resulted in saturated alcohol 62. The oxidation of 62 followed by reduction of 61 resulted in saturated alcohol 62. The oxidation of 62 led to an aldehyde, led to an aldehyde, the Wittig olefination of which provided the precursor 63 as a mixture of the Wittig olefination of which provided the precursor 63 as a mixture of isomers. The product of isomers. The product of photoinduced isomerization of this mixture was the trans-isomer 64. The photoinduced isomerization of this mixture was the trans-isomer 64. The target epiplakinic acid F (8) target epiplakinic acid F (8) was obtained by alkaline hydrolysis of ester 64 (Scheme 8). was obtained by alkaline hydrolysis of ester 64 (Scheme8).

Molecules 2017, 22, 1881 7 of 39 Molecules 2017, 22, 1881 7 of 39 Molecules 2017, 22, 1881 7 of 39

SchemeSchemeScheme 7. 7.7.Construction ConstructionConstruction of ofof 1,2-dioxolane1,2-dioxolane fr fragmentfragmentagment forfor epiplakinicepiplakinic epiplakinic acidacid acid FF F ((88 ().8). ).

SchemeScheme 8.8. AsymmetricAsymmetric synthesissynthesis ofof epiplakinicepiplakinic acidacid FF ((88).). Scheme 8. Asymmetric synthesis of epiplakinic acid F (8).

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The method of the preparation of andavadoic acid (76), a natural compound isolated from the spongesThe of method Plaxortis of theaff preparationsimplex, based of andavadoicon the Isayama acid (−76Mukaiyama), a natural reaction compound and isolated subsequent from cyclizationthe sponges was of knownPlaxortis [66]. aff The simplex starting, based substrate on the was Isayama-Mukaiyama epichlorohydrin (65), reaction which was and converted subsequent to epoxidecyclization 66 by was a knownsubsequent [66]. the The organomagnesium starting substrate wascompou epichlorohydrinnd addition and (65), cyclization which was with converted the help to ofepoxide alkaline.66 by The a subsequent regioselective the organomagnesiumopening of the epoxide compound cycle addition of 66 by and the cyclization lithium withsalt of the ethyl help propiolateof alkaline. in The the regioselective presence of openingBF3 resulted of the in epoxide the secondary cycle of alcohol66 by the 67 lithium in almost salt quantitative of ethyl propiolate yield. Alcoholin the presence 67 was of converted BF3 resulted into in lactone the secondary 68 by reaction alcohol 67within almostMe2CuLi, quantitative followed yield.by acidification. Alcohol 67 wasOxidation converted of lactone into lactone68 to 69,68 subsequentby reaction ring with opening, Me2CuLi, oxidation followed of hydroxyl by acidification. to the carbonyl Oxidation group, of andlactone methylation68 to 69, subsequent resulted ringin epoxy opening, ketone oxidation 70, which of hydroxyl was tothen the converted carbonyl group, to epoxy and methylationalkene 71. Isayama–Mukaiyamaresulted in epoxy ketone peroxidation,70, which wasthe thenbase-catalyzed converted tocyclization epoxy alkene of peroxide71. Isayama-Mukaiyama 72, leading to a mixtureperoxidation, of diastereomeric the base-catalyzed 1,2-dioxolanes cyclization 73/73a of peroxidefollowed by72, separation leading to and a mixture thioacylation of diastereomeric resulted in 1,2-dioxolanesa peroxy thioester73/ 73a74 whichfollowed was by converted separation into and andavadoic thioacylation acid resulted (76) by in asubsequent peroxy thioester reduction74 which and washydrolysis converted of ester into andavadoic75 (Scheme 9). acid (76) by subsequent reduction and hydrolysis of ester 75 (Scheme9).

Scheme 9. Synthesis of andavadoic acid ( 76).

The symbiont of beetle of the southern pine (Dendroctonus frontalis), actinomycetous bacterium The symbiont of beetle of the southern pine (Dendroctonus frontalis), actinomycetous bacterium produces mycangimycin peroxide (77) with pronounced fungicidal activity (Scheme 10) [67]. produces mycangimycin peroxide (77) with pronounced fungicidal activity (Scheme 10) [67]. Mycangimycin Mycangimycin effectively inhibits growth of Candida albicans wild type, C. albicans ATCC10231, effectively inhibits growth of Candida albicans wild type, C. albicans ATCC10231, amphotericin-resistant amphotericin-resistant strain C. albicans ATCC 200955, Saccharomyces cerevisiae and Ophiostoma minus [68]. strain C. albicans ATCC 200955, Saccharomyces cerevisiae and Ophiostoma minus [68].

Molecules 2017, 22, 1881 9 of 39 Molecules 2017,, 22,, 18811881 9 of 39

Scheme 10. Natural peroxide mycangimycin and its fungicidal activity. Scheme 10. Natural peroxide mycangimycin and its fungicidal activity. Scheme 10. Natural peroxide mycangimycin and its fungicidal activity. Two saturated analogs of mycangimycin were synthesized from alkene 78 and ester 79 (Scheme Two saturated analogs of mycangimycin were synthesized from alkene 78 and ester 79 (Scheme 11) [69].Two The saturated Kulinkovich analogs reaction of mycangimycin of 78 with were79 resulted synthesized in cyclopropane from alkene 8078, whichand esterformed79 11) [69]. The Kulinkovich reaction of 78 with 79 resulted in cyclopropane 80, which formed 1,2-dioxolane(Scheme 11)[ 6981]. by The a cobalt-catalyzed Kulinkovich reaction cleavage of 78 inwith the pr79esenceresulted of oxygen. in cyclopropane TfOH-catalyzed80, which reduction formed 1,2-dioxolane 81 by a cobalt-catalyzed cleavage in the presence of oxygen. TfOH-catalyzed reduction of1,2-dioxolane the alcohol 8181by by a silane cobalt-catalyzed led to 3,5-disubstituted cleavage in the 1,2-dioxolane presence of oxygen.82. The TfOH-catalyzedresult of desilylation reduction and of the alcohol 81 by silane led to 3,5-disubstituted 1,2-dioxolane 82. The result of desilylation and oxidationof the alcohol of the81 obtainedby silane alcohol led to 83 3,5-disubstituted is the first saturated 1,2-dioxolane analog of mycangimycin,82. The result of acid desilylation 84, which andcan oxidation of the obtained alcohol 83 is the first saturated analog of mycangimycin, acid 84, which can beoxidation converted of the into obtained ester 85. alcohol 83 is the first saturated analog of mycangimycin, acid 84, which can be converted into ester 85. be converted into ester 85. TiCl(OiPr) Co(acac) O O O 3 OH 2 O O TiCl(OiPr)3 OH Co(acac)O 2 O O OH O C5H9MgCl3 OH 2 2 OH C5H9MgCl 14 O2 OH O 5 THF9 EtOH2 14 OR 14 14 EtOH 14 OR O 14 91%THF 90% 81 14 OR 78 79 14 OR 80 90% OR 91% OR 80 90% OR 81 78 79 OR 80 OR O O O O H5IO6 O O O O H IO Et3SiH, TfOH O O TBAF, AcOH O O RuClH53IOH62O Et SiH, TfOH TBAF, AcOH RuCl H O Et3SiH, TfOH TBAF, AcOH CClRuCl/H O/CH3 H2OCN CH2Cl2 14 THF 14 4 2 3 CH Cl CCl4/H2O/CH3CN CH2Cl2 14 81%THF 14 4 88%2 3 66% OR 82 14 OH 83 66% 81% 83 88% 66% OR 82 OH 83 O O O O R = TBDPS O O O O R = TBDPS TMSCHN2 R = TBDPS TMSCHN2 14 MeOH 2 14 HO 14 MeOH MeO 14 HO O 84 81% MeO O 85 HO O 81% MeO O O 84 81% O 85

Scheme 11. TheThe synthesis synthesis of of saturated analogs of mycangimycin 84 and 85. Scheme 11. The synthesis of saturated analogs of mycangimycin 84 and 85. The diterpenoid peroxide 86, which has a weak fungicidal activity against C. albicans, was The diterpenoidditerpenoid peroxide peroxide86 86, which, which has has a weak a weak fungicidal fungicidal activity activity against againstC. albicans C. ,albicans was isolated, was isolatedThe fromditerpenoid the liverwort peroxide Jungermannia 86, which atrobrunneahas a weak (Schemefungicidal 12) activity [70]. Dinardokanshone against C. albicans B , (was87), isolatedfrom the from liverwort the Jungermannialiverwort Jungermannia atrobrunnea atrobrunnea(Scheme 12 )[(Scheme70]. Dinardokanshone 12) [70]. Dinardokanshone B (87), sesquiterpene B (87), sesquiterpeneisolated from theperoxide, liverwort isolated Jungermannia from the atrobrunnea roots and (Scheme rhizomes 12) of [70]. Nardostachys Dinardokanshone chinensis BBatal. (87), peroxide,sesquiterpene isolated peroxide, from the isolated roots and from rhizomes the roots of Nardostachys and rhizomes chinensis of Batal.Nardostachys(Valerianaceae) chinensis showed Batal. (Valerianaceae)sesquiterpene peroxide, showed significant isolated fromenhancement the roots effects and onrhizomes SERT activity of Nardostachys (Scheme 12) chinensis [71]. Batal. (Valerianaceae)significant enhancement showed significant effects on SERTenhancement activity(Scheme effects on 12 SERT)[71]. activity (Scheme 12) [71].

SchemeScheme 12. TerpeneTerpene peroxides 86 and 87. Scheme 12. Terpene peroxides 86 and 87.

Molecules 2017, 22, 1881 10 of 39 Molecules 2017, 22, 1881 10 of 39 Molecules 2017, 22, 1881 10 of 39 Synthetic 1,2-dioxolanes 88 showed high in vitrovitro activityactivity againstagainst helminthshelminths SchistosomaSchistosoma mansoni Synthetic 1,2-dioxolanes 88 showed high in vitro activity against helminths mansoni (Scheme 1313))[ [72].72]. (Scheme 13) [72].

R2 R3 R2 R3 R1 OR R O O OR 1 O O 88 88 R1, R2 = Me, Bu, -(CH2)5- R R = Me, Bu, -(CH ) - 1,R3 2= Me, CH2CH2Ph2 5 R = Me, CH CH Ph R3 = CH2CH22Ph, 2Bn R = CH2CH2Ph, Bn NTS S. mansoni IC50 < 20 M NTS S. mansoni IC < 20 M 50 Scheme 13. 1,2-Dioxolanes 88 exhibiting high activity against . Scheme 13. 1,2-Dioxolanes 88 exhibiting high activity against schistosomiasis. 5,5-Dimethyl 1,2-dioxolanes 88a were prepared by peroxidation of mesityl oxide (89) in the 5,5-Dimethyl 1,2-dioxolanes1,2-dioxolanes88a 88awere were prepared prepared by by peroxidation peroxidation of mesitylof mesityl oxide oxide (89) in(89 the) in basic the basic medium, followed by alkylation of the free hydroxyl group of 3-hydroxy-1,2-dioxolanes 90 medium,basic medium, followed followed by alkylation by alkyla of thetion free of hydroxyl the free group hydroxyl of 3-hydroxy-1,2-dioxolanes group of 3-hydroxy-1,2-dioxolanes90 (Scheme 14) [ 7390]. (Scheme 14) [73]. Synthesis of cyclohexyl derivatives 88b started from oxidation of alcohol 92 to an Synthesis(Scheme 14) of cyclohexyl[73]. Synthesis derivatives of cyclohexyl88b started derivatives from oxidation 88b started of alcohol from92 oxidationto an unsaturated of alcohol ketone 92 to 93an, unsaturated ketone 93, followed by Isayama–Mukaiyama peroxidation with formation of followedunsaturated by Isayama-Mukaiyamaketone 93, followed peroxidation by Isayama–Mukaiyama with formation of 1,2-dioxolaneperoxidation 94with. Further formation protection of 1,2-dioxolane 94. Further protection of hydroxyl group resulted in derivatives 88b (Scheme 14) [73]. of1,2-dioxolane hydroxyl group 94. Further resulted protection in derivatives of hydroxyl88b (Scheme group 14 resulted)[73]. in derivatives 88b (Scheme 14) [73].

Scheme 14. Synthesis of anthelmintic 1,2-dioxolanes 88. Scheme 14. Synthesis of anthelmintic 1,2-dioxolanes 88.. The series of tricyclic monoperoxides 97 with 1,2-dioxolane moiety showed a high The series of tricyclic monoperoxides 97 with 1,2-dioxolane moiety showed a high anti-schistosomalThe series of tricyclicactivity. monoperoxides The maximum97 activitywith 1,2-dioxolane was observed moiety for compound showed a high 97a, anti-schistosomal which revealed anti-schistosomal activity. The maximum activity was observed for compound 97a, which revealed activity.high The burden maximum reductions activity by was 82.8% observed in S. formansoni compound mouse97a model, which (Scheme revealed 15) high [74]. worm Peroxides burden 97 high worm burden reductions by 82.8% in S. mansoni mouse model (Scheme 15) [74]. Peroxides 97 reductionscan be obtained by 82.8% from in βS., δ mansoni-triketonesmouse 96 modeland hydrogen (Scheme peroxide15) [74]. Peroxides with use of97 eithercan be sulfuric obtained acid from [75],β, can be obtained from β, δ-triketones 96 and hydrogen peroxide with use of either sulfuric acid [75], δor-triketones boron trifluoride96 and hydrogen [76] as cata peroxidelyst and with co-solvent use of either(Scheme sulfuric 15). acid [75], or boron trifluoride [76] as catalystor boron and trifluoride co-solvent [76] (Scheme as catalyst 15). and co-solvent (Scheme 15).

Molecules 2017, 22, 1881 11 of 39 Molecules 2017, 22, 1881 1111 of of 39 39

Scheme 15. Synthesis of tricyclic monoperoxides 97 with high anti-schistosomal activity. SchemeScheme 15. 15.Synthesis Synthesis of of tricyclic tricyclic monoperoxidesmonoperoxides 97 with high anti-sch anti-schistosomalistosomal activity. activity.

3. 1,2,4-Trioxolanes (Ozonides) 3.3. 1,2,4-Trioxolanes 1,2,4-Trioxolanes (Ozonides) (Ozonides) Various tetrasubstituted 1,2,4-trioxolanes (ozonides) have become the breakthrough in the field VariousVarious tetrasubstituted tetrasubstituted 1,2,4-trioxolanes 1,2,4-trioxolanes (ozonides)(ozonides) havehave become the breakthrough breakthrough in in the the field field of biologically active synthetic peroxides. Nowadays ozonides are considered as the most promising ofof biologically biologically active active synthetic synthetic peroxides. peroxides. NowadaysNowadays ozonidesozonides are considered as as the the most most promising promising candidates in the treatment of helminth diseases (Scheme 16). The 100% worm burden reductions candidatescandidates in in the the treatment treatment of of helminth helminth diseasesdiseases (Scheme(Scheme 1616).). The 100% worm worm burden burden reductions reductions were observed with a single oral dose of 1000 mg/kg OZ78 (98) in caproni-infected mice. werewere observed observed with with a a single single oral oral dose dose of of 1000 1000 mg/kg mg/kg OZ78 ( 98)) in in EchinostomaEchinostoma caproni caproni-infected-infected mice. mice. A single dose of 100 mg/kg OZ78 (98) resulted in 100% worm burden reductions against juvenile and A single dose of 100 mg/kg OZ78 (98) resulted in 100% worm burden reductions against juvenile and Aadult single Fasciola dose of hepatica 100 mg/kg-mouseOZ78 model ( 98[77].) resulted Single oral in 100%doses wormof 100 mg/kg burden OZ78 reductions (98) is efficient against against juvenile adult Fasciola hepatica-mouse model [77]. Single oral doses of 100 mg/kg OZ78 (98) is efficient against andadult adult -resistantFasciola hepatica-mouse F. modelhepatica [77-infected]. Single rats oral [78]. doses Later, of 100the mg/kgefficacy OZ78 of 1,2,4-trioxolane (98) is efficient adult triclabendazole-resistant F. hepatica-infected rats [78]. Later, the efficacy of 1,2,4-trioxolane againstOZ78 adult(98) against triclabendazole-resistant an experimental infectionF. hepatica with-infected Fasciola rats hepatica [78]. Later,in sheep the was efficacy confirmed of 1,2,4-trioxolane [79,80]. It OZ78 (98) against an experimental infection with Fasciola hepatica in sheep was confirmed [79,80]. It OZ78was (found98) against that anthe experimentalspiroadamantane infection fragment with andFasciola the hepaticacarboxylin group sheep in was the confirmed OZ78 (98 [) 79are,80 ]. was found that the spiroadamantane fragment and the carboxyl group in the OZ78 (98) are It wasnecessary found for that activity the spiroadamantane against F. hepatica fragment [81]. and the carboxyl group in the OZ78 (98) are necessary fornecessary activity againstfor activityF. hepatica against[ 81F.]. hepatica [81].

Scheme 16. Tetrasubstituted synthetic ozonides with the highest anthelmintic activity. SchemeScheme 16. 16.Tetrasubstituted Tetrasubstitutedsynthetic synthetic ozonidesozonides withwith the highest anthelmintic activity. activity. The ozonides OZ78 (98) and OZ288 (99) showed low toxicity and high efficiency against helminthTheThe ozonides ozonidescultures OZ78 SchistosomaOZ78 (98 )(98 and) mansoniand OZ288 OZ288 (and99) showed(S.99 )japonicum showed low toxicity harbouredlow toxicity and highin andmice efficiency high and efficiencyhamsters against helminthwithagainst a cultureshelminthsingle oralSchistosoma cultures dose of mansoni200Schistosoma mg/kgand [82,83]. mansoniS. japonicum Antichistosomal and harbouredS. japonicum activity in harboured mice of and OZ78 hamsters in (98 mice) against withand S.hamsters a singlejaponicum oral with was dose a ofsingle 200 mg/kg oral dose [82 ,of83 200]. Antichistosomal mg/kg [82,83]. Antichistosomal activity of OZ78 activity (98) against of OZ78S. ( japonicum98) againstwas S. japonicum confirmed was in

Molecules 2017, 22, 1881 12 of 39 Molecules 2017, 22, 1881 12 of 39 experimentsconfirmed in in experiments mice and rabbits in mice [84 and]. Later, rabbits the [84]. promising Later, the ozonide promising OZ418 ozonide (100) OZ418 with high (100 activity) with againsthigh activity both helminths against both of S.helminths mansoni andof S.S. mansoni haematobium and S. washaematobium discovered was [85 discovered]. [85]. SynthesisSynthesis of of tetrasubstituted tetrasubstituted unsymmetrical unsymmetrical ozonides ozonides was discoveredwas discovered by Griesbaum by Griesbaum and colleagues and incolleagues 1995 (Scheme in 1995 17 ,(Scheme top) [86 17,,87 ].top) Later [86,87]. this Later method this was method used was for theused diastereoselective for the diastereoselective synthesis ofsynthesis tetrasubstituted of tetrasubstituted ozonides 103 ozonides. Peroxides 103103. Peroxideswere prepared 103 were by ozonolysisprepared ofby 2-adamantanoneozonolysis of O-methyl2-adamantanone oxime ( 101O-methyl) in the oxime presence (101 of) substitutedin the presence cyclohexanones of substituted102 cyclohexanones(Scheme 17, bottom) 102 (Scheme [88,89 ]. 1,2,4-Trioxolane17, bottom) [88,89]. ring 1,2,4-Trioxolane in compounds ring103 inis compounds resistant to103 the is resistant action of to athe wide action range of a wide of reagents, range whichof reagents, allows which to proceed allows a to variety proceed of modifications a variety of modifications of the cyclohexane of the cycl substituentohexane [substituent88]. [88].

Griesbaum co-ozonolysis R OCH O O 1 3 R4 O3 R1 R3 OCH3 N O O N O R2 R3 R2 R4

Synthesis of tetrasubstituted unsymmetrical ozonides reactions in which OCH3 O O the peroxide ring O3 N O R remains intact O CH2Cl2 R o 101 102 78 C 103 SchemeScheme 17.17. SynthesisSynthesis of tetrasubstituted unsymmetrical unsymmetrical ozonides. ozonides.

4.4. 1,2-Dioxanes 1,2-Dioxanes AA number number of of compounds compounds containing containing 1,2-dioxane 1,2-dioxane fragment fragment isolated isolated from thefromPlakinidae the Plakinidaesponges sponges showed highshowed fungicidal high andfungicidal anti-trypanosomal and anti-trypanosomal activity. Plakinic activity. acid BPlakinic (104) exhibited acid B good(104) fungicidalexhibited activitygood againstfungicidalSaccharomyces activity against cerevisiae Saccharomycesand Penicillium cerevisiae atrovenetum and Penicillium(Scheme 18 atrovenetum) [56]. The acid(Scheme105 in 18) vitro [56].inhibits The acid 105 in vitro inhibits the growth of fungi Aspergillus fumigatus with IC90 = 5.6 µg/mL [58]. the growth of fungi Aspergillus fumigatus with IC90 = 5.6 µg/mL [58]. Compounds 106 and 107 were Compounds 106 and 107 were weakly active against Staphylococcus aureus [90]. weakly active against Staphylococcus aureus [90]. 11,12-Didehydro-13-oxo-plakortide Q (108) was 11,12-Didehydro-13-oxo-plakortide Q (108) was more active against Trypanosoma brucei [91]. more active against Trypanosoma brucei [91]. Plakortide F acid (PFA) (109) showed high activity Plakortide F acid (PFA) (109) showed high activity against Candida albicans, Cryptococcus neoformans against Candida albicans, Cryptococcus neoformans and A. fumigatus [21]. Plakortides 110 and 111 also and A. fumigatus [21]. Plakortides 110 and 111 also demonstrated high activity against a number of demonstrated high activity against a number of fungi [92]. Significant fungicidal activity of mixture of fungi [92]. Significant fungicidal activity of mixture of peroxyketal acids isolated from sea sponges peroxyketal acids isolated from sea sponges was also reported [93]. was also reported [93]. A series of peroxyterpenes was isolated from the sponges Diacarnus bismarckensis, the most A series of peroxyterpenes was isolated from the sponges Diacarnus bismarckensis, the most active of which, (+)-muqubilone B (112) and sigmosceptrellin B (113) showed high activity active of which, (+)-muqubilone B (112) and sigmosceptrellin B (113) showed high activity against against Trypanosoma brucei [94]. (+)-Muqubilone B (112) and muqubilin (114) (isolated from Trypanosoma brucei [94]. (+)-Muqubilone B (112) and muqubilin (114) (isolated from the sponges the sponges Prianos [95]) were in vitro effective against herpes (HSV-1), muqubilin (114) and Prianos [95]) were in vitro effective against herpes virus (HSV-1), muqubilin (114) and (−)-sigmosceptrellin B (113) exhibited in vitro activity against Toxoplasma gondii (Scheme 19)[96]. (−)-sigmosceptrellin B (113) exhibited in vitro activity against Toxoplasma gondii (Scheme 19) [96]. Muqubilin (114) possesses herbicidal activity against tobacco Nicotiana tabacum [97], as well as Muqubilin (114) possesses herbicidal activity against tobacco Nicotiana tabacum [97], as well as 115 116 epimuqubilinepimuqubilin ( (115)) showedshowed NONO inhibitoryinhibitory activityactivity [[98].98]. Mycaperoxide Mycaperoxide В B ( (116)) displays displays high high antiviral antiviral activityactivity against against vesicularvesicular stomatitisstomatitis virusvirus andand herpesherpes simplex virus type-1 (HCV-1) [99]. [99]. SeveralSeveral syntheticsynthetic approaches approaches to to plakinic plakinic acids acids and and their their derivatives derivatives containing containing 1,2-dioxane 1,2-dioxane ring ringwere were described. described. Natural Natural 6-epiplakortolide 6-epiplakortolide E (127 E (127) was) was firstly firstly synthesized synthesized from from available available 1-bromo-10-phenyldecane1-bromo-10-phenyldecane ( 117) in in 10 10 steps steps by by Diels–Alder Diels-Alder reaction reaction with with singlet singlet oxygen oxygen followed followed by byiodolactonization iodolactonization (Scheme (Scheme 20) [100].20)[100 In ].the In first the st firstage, the stage, addition the addition of the organomagnesium of the organomagnesium reagent reagentto the unsaturated to the unsaturated ketone ketone resulted resulted in enone in enone 118, 118which, which was was converted converted to a to tertiary a tertiary alcohol alcohol 119119. . HydroborationHydroboration ofof 119119 ledled toto dioldiol 120,, protectionprotection of of hydroxyl hydroxyl grou groupp of of which which provide provide silyl silyl ether ether 121121. . Diels-AlderDiels–Alder reactionreaction ofof dienediene 122122 preparedprepared byby dehydrationdehydration of 121 with singlet singlet oxygen oxygen resulted resulted in in diastereomericdiastereomeric 1,2-dioxanes1,2-dioxanes 123a123а and 123b. Deprotected diastereomer diastereomer 124124 waswas oxidized oxidized to to acid acid 125125, , subsequentsubsequent iodolactonizationiodolactonization of thisthis acid gave bicycle 126. Desirable Desirable 6-epiplakortolide 6-epiplakortolide E E (127 (127) )was was formedformed asas resultresult ofof radicalradical reductionreduction ofof iodine-containingiodine-containing bicycle 126.. It It was was noted noted that that related related plakortolideplakortolide G G ( 128(128)) is is activeactive againstagainst thethe protozoaprotozoa ToxoplasmaToxoplasma gondiigondii [[101].101].

Molecules 2017, 22, 1881 13 of 39 Molecules 2017,, 22,, 18811881 13 of 39

SchemeScheme 18. 18.1,2-Dioxanes 1,2-Dioxanes1,2-Dioxanes isolated isolatisolated from from thethe spongessponges PlakinidaePlakinidae;; ; theirtheir their antifungal,antifungal, antifungal, antibacterialantibacterial antibacterial andand and anti-trypanosomalanti-trypanosomal activity activity is is also also shown. shown.

O O H O O O

HO2C O H muqubilone B (112) muqubilone B (112) O O H T. brucei ICIC50 = 2 g/mL herpes simplex type 1 (HSV-1) ED50 =30 g/mL CO2H

sigmosceptrellin B (113)) O O H H T. brucei ICIC50 = 0.2 g/mL Toxoplasma gondii >90% inhibition 0.1 M CO2H muqubilin (114)) O O H herpes simplex type 1 (HSV-1) ED50 =7.5 g/mL Toxoplasma gondii >90% inhibition 0.1 M Toxoplasma gondii >90% inhibition 0.1 M CO2H гербицидный эффект 66% Nicotiana tabacum 6.4 M epimuqubilin A (115)) H NO inhibitory activity IC50 = 7.4 M

HO O O H

CO2H mycaperoxide B (116))

herpes simplex type 1 (HSV-1) ICIC50 =0.25-1.0 g/mL vesicular stomatitis virus IC =0.25-1.0 g/mL vesicular stomatitis virus IC50 =0.25-1.0 g/mL

SchemeScheme 19. 19.Muqubilin MuqubilinMuqubilin ( ((114114))) andandand related related naturalnatural natural peroxides.peroxides. peroxides.

Molecules 2017, 22, 1881 14 of 39 Molecules 2017, 22, 1881 14 of 39

SchemeScheme 20.20. SynthesisSynthesis of 6-epiplakortolide Е E ( (127127).).

AsymmetricAsymmetric synthesissynthesis of of alkoxy-1,2-dioxane alkoxy-1,2-dioxane 136136 relatedrelated to plakortolides to plakortolides was realized was realized in 8 steps in 8from steps carbonyl from carbonyl compounds compounds 129 and 129130 (Schemeand 130 21)(Scheme [102]. Enantioselecti21)[102]. Enantioselectiveve aldol reaction aldol in first reaction step inresulted first step in aldol resulted 131 inwhich aldol was131 convertedwhich was into converted protected diol into 132 protected in three diol steps.132 Diastereomericin three steps. Diastereomeric1,2-dioxanes 133a 1,2-dioxanes and 133b133a wereand formed133b were by formedselective by ozonolysis selective ozonolysisof double ofbond double of bond132. ofHydrozirconation132. Hydrozirconation of 133а of with133a followingwith following treatment treatment by iodine by led iodine to the led formation to the formation of vinyl ofiodide vinyl iodide134, followed134, followed cross-coupling cross-coupling of one of oneresulted resulted in 1,2-dioxane in 1,2-dioxane 135135. Deprotection. Deprotection of of135135 providedprovided desirable peroxide 136. desirable peroxide 136. Natural endoperoxide 9,10-dihydroplakortin (148) and diastereomer 149 were synthesized Natural endoperoxide 9,10-dihydroplakortin (148) and diastereomer 149 were synthesized through Evans’ chiral auxiliary chemistry (Scheme 22) [103]. Alkylation of oxazolidinone 137 and through Evans’ chiral auxiliary chemistry (Scheme 22)[103]. Alkylation of oxazolidinone 137 subsequent reduction of 138 led to alcohol 139, which was transformed into acrylic ester 140 and subsequent reduction of 138 led to alcohol 139, which was transformed into acrylic ester 140 (predominantly in E-configuration) by oxidation and Horner–Wadsworth–Emmons olefination. The (predominantly in E-configuration) by oxidation and Horner-Wadsworth-Emmons olefination. ester 140 was reduced into corresponding alcohol, which was converted into iodide 141, alkylation The ester 140 was reduced into corresponding alcohol, which was converted into iodide 141, alkylation of oxazolidinone by which resulted in derivative 142. The cleavage and olefination of 142 provided of oxazolidinone by which resulted in derivative 142. The cleavage and olefination of 142 provided the ester 143. The reduction of 143 furnished alcohol 144 followed by Sharpless epoxidation and the ester 143. The reduction of 143 furnished alcohol 144 followed by Sharpless epoxidation and protection of primary hydroxy-group with formation of epoxide 145. Isayama–Mukaiyama protectionperoxidation of primary of epoxide hydroxy-group 145 afforded with mixture formation of ofdiastereomeric epoxide 145. Isayama-Mukaiyama1,2-dioxanes 146 andperoxidation 147 which ofwere epoxide independently145 afforded transformed mixture of diastereomericinto 9,10-dihydroplakortin 1,2-dioxanes (148146) and 1476-epiwhich-dihydroplakortin were independently (149). transformed into 9,10-dihydroplakortin (148) and 6-epi-dihydroplakortin (149).

Molecules 2017, 22, 1881 15 of 39 Molecules 2017, 22, 1881 15 of 39 Molecules 2017, 22, 1881 15 of 39

SchemeScheme 21.21. AsymmetricAsymmetric synthesis ofof 1,2-dioxane1,2-dioxane 136 136. .

Scheme 22. 148 149 Scheme 22.Synthesis Synthesisof of naturalnatural endoperoxideendoperoxide 9,10-dihydroplakortin ( (148)) and and its its diastereomer diastereomer 149. . Scheme 22. Synthesis of natural endoperoxide 9,10-dihydroplakortin (148) and its diastereomer 149.

Molecules 2017, 22, 1881 16 of 39 Molecules 2017, 22, 1881 16 of 39

MoleculesInIn the the 2017 synthesis synthesis, 22, 1881 of of diastereomeric diastereomeric plakortolidesplakortolides 160160 andand 161161, ,the the key key steps steps are are construction construction16 of 39 of of protectedprotected diol diol155 155from from protected protected 2-methyl 2-methyl glycidolglycidol 154 and vinyl vinyl bromide bromide 152152, diastereoselective, diastereoselective In the synthesis of diastereomeric plakortolides 160 and 161, the key steps are construction of MukaiyamaMukaiyama addition addition of of aldehyde aldehyde156 156with with formation formation of of ester ester157 157and and hydroperoxidation hydroperoxidation of of alkene alkene158 protected diol 155 from protected 2-methyl glycidol 154 and vinyl bromide 152, diastereoselective with158 subsequent with subsequent cyclization cyclization of 159 of(Scheme 159 (Scheme 23)[ 10423) ].[104]. Mukaiyama addition of aldehyde 156 with formation of ester 157 and hydroperoxidation of alkene 158 with subsequent cyclization of 159 (Scheme 23) [104].

SchemeScheme 23. 23.Synthesis Synthesis ofof diastereomericdiastereomeric plakortolides plakortolides 160160 andand 161161. . Scheme 23. Synthesis of diastereomeric plakortolides 160 and 161. Synthesis of analogs of plakinic acids, 1,2-dioxanes 166 with a pronounced anti-trypanosomal Synthesis of analogs of plakinic acids, 1,2-dioxanes 166 with a pronounced anti-trypanosomal activitySynthesis was proposed of analogs from of E plakinic-hexen-4-ol acids, (162 1,2-dioxanes) (Scheme 24) 166 [105]. with Swern a pronounced oxidation anti-trypanosomal of alcohol 162 and activity was proposed from E-hexen-4-ol (162) (Scheme 24)[105]. Swern oxidation of alcohol 162 subsequentactivity was Wittig-olefination proposed from E-hexen-4-ol led to ester ( 162163). (SchemeThe reaction 24) [105]. of unsaturated Swern oxidation scaffold of alcohol163 with 162 singlet and 163 163 andoxygensubsequent subsequent and Wittig-olefinationfollowing Wittig-olefination cyclization led to ledprovided ester to ester163 1,2-dioxane. The .reaction The reaction164 of, unsaturatedwhich of unsaturatedwas scaffoldhydrolyzed 163 scaffold withto acid singlet 165with . singletDerivativesoxygen oxygen and 166 andfollowing were following prepared cyclization cyclization from provided ester provided 164 1,2-dioxane by 1,2-dioxane consistent 164, 164 whichozonolysis,, which was washydrolyzed reductive hydrolyzed cleavageto acid to acid 165 and.165 . DerivativesWittigDerivatives reaction.166 166were Compounds were prepared prepared 166 from exhibitedfrom ester ester164 high 164by activity consistentby consistent against ozonolysis, ozonolysis,T. brucei reductive brucei reductive BF427. cleavage cleavage and and Wittig reaction.Wittig Compoundsreaction. Compounds166 exhibited 166 exhibited high activity high activity against againstT. brucei T. brucei bruceiBF427. BF427.

Scheme 24. Synthesis of 1,2-dioxanes 166 with high anti-trypanosomal activity. SchemeScheme 24. 24.Synthesis Synthesis of of 1,2-dioxanes 1,2-dioxanes 166 withwith high high anti-trypanosomal anti-trypanosomal activity. activity. Diastereomeric cyclic peroxides 171, one of which is the methyl ester of the mycaperoxide B Diastereomeric cyclic peroxides 171, one of which is the methyl ester of the mycaperoxide B (116Diastereomeric), were prepared cyclic from peroxides protected171 hydroxyperoxide, one of which 167 is the (Scheme methyl 25) ester [106]. of In the the mycaperoxide first step, (116), were prepared from protected hydroxyperoxide 167 (Scheme 25) [106]. In the first step, B(116), were prepared from protected hydroxyperoxide 167 (Scheme 25)[106]. In the first step,

Molecules 2017, 22, 1881 17 of 39 Molecules 2017, 22, 1881 17 of 39 Molecules 2017, 22, 1881 17 of 39 peroxideperoxide167 167was was oxidized oxidized to aldehydeto aldehyde168 168, which, which was was converted converted into into unsaturated unsaturated ester ester169 by169 Wittig by reaction.Wittigperoxide Hydroperoxidereaction. 167 was Hydroperoxide oxidized170 synthesized to aldehyde 170 synthesized by 168 deprotection, which bywas ofdeprotection converted169 wascyclized into of unsaturated169 into was 1,2-dioxane cyclized ester 169 171into byand oxolane1,2-dioxaneWittig172 reaction.by 171 the and actionHydroperoxide oxolane of triethylamine. 172 by 170the actionsynthesized of triethylamine. by deprotection of 169 was cyclized into 1,2-dioxane 171 and oxolane 172 by the action of triethylamine.

SchemeScheme 25. 25. SynthesisSynthesis of diastereomeric peroxides peroxides 171171. . Scheme 25. Synthesis of diastereomeric peroxides 171. 5. 1,2-Dioxenes 5. 1,2-Dioxenes5. 1,2-Dioxenes The plant Chenopodium ambrosioides is used for the production of essential chenopodium oil, TheThe plant plantChenopodium Chenopodium ambrosioides ambrosioides isis usedused for the the production production of of essential essential chenopodium chenopodium oil, oil, which has been used as an anthelmintic agent for a long time [107,108]. The first isolation of the most whichwhich has has been been used used as as an an anthelmintic anthelmintic agent agent forfor aa long time [107,108]. [107,108]. The The first first isolation isolation of ofthe the most most active component- (174), from the Chenopodium ambrosioides and the determination of its activeactive component-ascaridole component-ascaridole ( 174(174),), from from thethe ChenopodiumChenopodium ambrosioides ambrosioides andand the the determination determination of its of its structure was dated to the beginning of the last century [109–112]. In the 1950s, the ascaridole (174) structurestructure was was dated dated to to the the beginning beginning of of thethe lastlast centurycentury [109–112]. [109–112]. In In the the 1950s, 1950s, the the ascaridole ascaridole (174 (174) ) was completely characterized (Scheme 26) [113,114]. waswas completely completely characterized characterized (Scheme (Scheme 26 26))[ 113[113,114].,114]. The first laboratory synthesis of ascaridole (174) was performed via photo-induced addition of The first laboratory synthesis of ascaridole (174) was performed via photo-induced addition of singletThe firstoxygen laboratory to terpene synthesis 173 by Schenck of ascaridole in 1944 ( 174(Scheme) was 26) performed [115]. Later, via this photo-induced reaction was addition realized of singlet oxygen to terpene 173 by Schenck in 1944 (Scheme 26) [115]. Later, this reaction was realized singletin an oxygenindustrial to scale, terpene because173 by ascaridole Schenck was in 1944 of great (Scheme importance 26)[115 as]. an Later, anthelmintic this reaction agent was [116]. realized The in an industrial scale, because ascaridole was of great importance as an anthelmintic agent [116]. The inmethod an industrial for the scale, preparation because of ascaridole ascaridole was using of greatsinglet importance oxygen generated as an anthelmintic in situ from agent sodium [116 ]. method for the preparation of ascaridole using singlet oxygen generated in situ from sodium Themolybdate method forand thehydrogen preparation peroxide of ascaridoleis known [117]. using singlet oxygen generated in situ from sodium molybdatemolybdate and and hydrogen hydrogen peroxide peroxide is is known known [[117].117].

Scheme 26. Ascaridole synthesis (174). SchemeScheme 26. 26. AscaridoleAscaridole synthesis ( (174174).).

It was shown that ascaridole (174) at concentration 4 mM almost completely inhibits the growth It wasIt was shown shown that that ascaridole ascaridole ( 174(174)) at at concentrationconcentration 4 4 mM mM almost almost completely completely inhibits inhibits the the growth growth of fungi Sclerotium rolfsii [118]. Presently, the side effects of ascaridole on the of fungiof fungiSclerotium Sclerotium rolfsii rolfsii[118 [118].]. Presently, Presently, the the side side effects effects of ascaridoleof ascaridole on on the the gastrointestinal gastrointestinal tract tract have have been described, and ascaridole is currently not used [119]. beenhave described, been described, and ascaridole and ascarido is currentlyle is currently not used not [used119]. [119]. In 1990, Gunasekera with colleagues isolated 1,2-dioxenes 175 and 176 from sea sponge Plakortis InIn 1990, 1990, Gunasekera Gunasekera with with colleagues colleagues isolated isolated 1,2-dioxenes 1,2-dioxenes 175 and175 176and from176 sea spongefrom sea Plakortis sponge angulospiculatus (Scheme 27) [120]. It was shown that these natural peroxides exhibit antifungal Plakortisangulospiculatus angulospiculatus (Scheme(Scheme 27) [120]. 27)[ 120It was]. It wasshown shown that thatthese these natural natural peroxides peroxides exhibit exhibit antifungal antifungal activityactivity against against Candida Candida albicansalbicans (MIC(MIC == 1.61.6 µg/mL).µg/mL). activity against Candida albicans (MIC = 1.6 µg/mL).

Molecules 2017, 22, 1881 18 of 39 MoleculesMolecules 20172017,, 2222,, 18811881 1818 ofof 3939

O O O O O O O O COOH COOH COOH COOH

175 176 175 176 Candida albicans MIC = 1.6 µg/mL Candida albicans MIC = 1.6 µg/mL

SchemeSchemeScheme 27. 27.27. Antifungal AntifungalAntifungal naturalnatural 1,2-dioxenes 1,2-dioxenes 175175,, , 176176176.. .

The total synthesis of stereoisomeric 1,2-dioxenes 185 was performed in 18 steps with a total TheThe total total synthesis synthesis of of stereoisomeric stereoisomeric 1,2-dioxenes 1,2-dioxenes185 185was was performed performed in 18in steps18 steps with with a total a total yield yield of 2.8% (Scheme 28) [121]. The treatment of hydroxy ester 177 with tert-butyldiphenylsilyl yield of 2.8% (Scheme 28) [121]. The treatment of hydroxy ester 177tert with tert-butyldiphenylsilyl ofchloride 2.8% (Scheme followed 28 )by [121 DIBAL]. The reduction treatment and of replacement hydroxy ester of 177hydroxylwith by -butyldiphenylsilyliodine provided iodide chloride 178, followedchloride by followed DIBAL by reduction DIBAL reduction and replacement and replacement of hydroxyl of byhydroxyl iodine by provided iodine iodideprovided178 iodide, which 178 was, whichwhich waswas convertedconverted intointo aldehydealdehyde 179179 byby subsequentsubsequent asymmetricasymmetric alkylation,alkylation, reductionreduction ofof preparedprepared converted into aldehyde 179 by subsequent asymmetric alkylation, reduction of prepared amide into amideamide intointo alcoholalcohol andand SwernSwern oxidation.oxidation. AlkeneAlkene 180180 waswas synthesizedsynthesized fromfrom sulfonesulfone derivativederivative ofof alcohol and Swern oxidation. Alkene 180 was synthesized from sulfone derivative of aldehyde 179 aldehydealdehyde 179179 toto obtainobtain mainlymainly transtrans-isomer.-isomer. DeprotectionDeprotection ofof 180180,, nucleophilicnucleophilic substitutionsubstitution ofof to obtain mainly trans-isomer. Deprotection of 180, nucleophilic substitution of hydroxyl by iodine, hydroxylhydroxyl byby iodine,iodine, subsequentsubsequent substitutionsubstitution ofof ioiodinedine byby cyano-groupcyano-group andand reductionreduction ofof cyano-groupcyano-group subsequentled to aldehyde substitution 181 which of iodine was then by cyano-group transformed andintoreduction alkyne 182 of by cyano-group PPh3/CBr4 treatment led to aldehyde and HBr181 led to aldehyde 181 which was then transformed into alkyne 182 by PPh3/CBr4 treatment and HBr which was then transformed into alkyne 182 by PPh /CBr treatment and HBr elimination. The synthesis elimination.elimination. TheThe synthesissynthesis ofof enoneenone 183183 waswas performedperformed3 4 byby additionaddition ofof ethylcuprateethylcuprate followedfollowed byby of enone 183 was performed by addition of ethylcuprate followed by propionyl chloride to alkyne 182. propionylpropionyl chloridechloride toto alkynealkyne 182182.. TheThe dienediene 184184 waswas preparedprepared predominantlypredominantly inin transtrans-conformation-conformation The diene 184 was prepared predominantly in trans-conformation by condensation of enone 183 with byby condensationcondensation ofof enoneenone 183183 withwith lithiumlithium saltsalt ofof propargypropargyll phosphonatephosphonate withwith subsequentsubsequent lithiumhydroboration.hydroboration. salt of propargyl EneEne reactionreaction phosphonate ofof dienediene with 184184 subsequentwithwith singletsinglet hydroboration. oxygenoxygen andand methylationmethylation Ene reaction byby of diazomethanediazomethane diene 184 with singletresultedresulted oxygen inin 1,2-dioxenes1,2-dioxenes and methylation 185185аа andand by 185b diazomethane185b.. resulted in 1,2-dioxenes 185a and 185b.

SchemeSchemeScheme 28. 28.28. Synthesis SynthesisSynthesis ofof stereoisomericstereoisomeric 1,2-dioxenes 1,2-dioxenes 185185185.. .

Molecules 2017, 22, 1881 19 of 39 Molecules 2017, 22, 1881 19 of 39 Molecules 2017, 22, 1881 19 of 39 The cyclic peroxide shuangkangsu ( 186) isolated from the buds of Lonicera japonica showed high The cyclic peroxide shuangkangsu (186) isolated from the buds of Lonicera japonica showed high antiviral activityactivity againstagainst respiratory respiratory syncytial syncytial virus virus on theon cellthe linescell andlines influenza and influenza virus in virus the chicken in the antiviral activity against respiratory syncytial virus on the cell lines and influenza virus in the chickenembryos embryos (Scheme (Scheme 29)[122 ].29) [122]. chicken embryos (Scheme 29) [122].

Scheme 29. PeroxidePeroxide shuangkangsu ( 186) isolated from Lonicera japonica. Scheme 29. Peroxide shuangkangsu (186) isolated from Lonicera japonica. Ergosterol peroxide (187) isolated from different natural sources including the fungi Pycnoporus Ergosterol peroxide peroxide (187 (187) isolated) isolated from from different different natural natural sources sourcesincluding including the fungi Pycnoporus the fungi cinnabarinus demonstrated moderate antiviral activity against Herpes simplex и Polio virus [123], and Pycnoporus cinnabarinus demonstrated moderate antiviral activity against Herpes simplex and Polio virus [123], alsocinnabarinus antifungal demonstrated activity against moderate pathogenic antiviral activityfungi Microsporum against Herpes canis simplex, Trichophyton и Polio virus rubrum [123], andand and also antifungal activity against pathogenic fungi Microsporum canis, Trichophyton rubrum and Epidermophytonalso antifungal floccosum activity (Schemeagainst pathogenic30) [124]. Ergost fungierol Microsporum peroxide acetate canis, 189Trichophyton was synthesized rubrum withand Epidermophyton floccosum (Scheme 30)[124]. Ergosterol peroxide acetate 189 was synthesized with quantitativeEpidermophyton yield floccosum by photo-ox (Schemeidation 30) [124]. of Ergostergosterolerol peroxide acetate acetate188 in 189 the was presence synthesized of tritylwith quantitativequantitative yieldyield by photo-oxidationby photo-oxidation of ergosterol of ergosterol acetate 188 acetatein the presence188 in ofthe trityl presence tetrafluoroborate of trityl tetrafluoroborate (Scheme 30) [125]. (Schemetetrafluoroborate 30)[125]. (Scheme 30) [125].

Scheme 30. Ergosterol peroxide (187), exhibited antiviral and antifungal activities and synthesis of its Scheme 30. Ergosterol peroxide (187), exhibited antiviral and antifungal activities and synthesis of its derivatives.Scheme 30. Ergosterol peroxide (187), exhibited antiviral and antifungal activities and synthesis of itsderivatives. derivatives. Analogs of ergosterol peroxide without multiple bonds in the side chain 194 were obtained by Analogs of ergosterol peroxide without multiple bonds in the side chain 194 were obtained by eosinAnalogs Y catalyzed of ergosterol photooxidation peroxide of withoutsteroids multiple191 followed bonds by in hydrolysis the side chain and 194oxidation.were obtained Peroxides by eosin Y catalyzed photooxidation of steroids 191 followed by hydrolysis and oxidation. Peroxides 194eosin showed Y catalyzed significant photooxidation ability to inhibit of steroids the grown191 followed of hepatitis by hydrolysis B virus (Scheme and oxidation. 31) [126]. Peroxides 194 194 showed significant ability to inhibit the grown of hepatitis B virus (Scheme 31) [126]. showed significant ability to inhibit the grown of hepatitis B virus (Scheme 31)[126].

Molecules 2017, 22, 1881 20 of 39 Molecules 2017, 22, 1881 20 of 39

SchemeScheme 31. 31.Synthesis Synthesis ofof 194194,, antiviral analogs analogs of of ergosterol ergosterol peroxide. peroxide.

A number of 1,2-dioxenes 196 with simpler structure were synthesized from 1,3-butadienes 195. A number of 1,2-dioxenes 196 with simpler structure were synthesized from 1,3-butadienes 195. Epoxidation of 196 resulted in 1,2-dioxanes 197 and 198. These peroxides exhibit moderate Epoxidation of 196 resulted in 1,2-dioxanes 197 and 198. These peroxides exhibit moderate antifungal antifungal activity against Candida family (Scheme 32) [127]. Later, a wide range of derivatives 196, activity against Candida family (Scheme 32)[127]. Later, a wide range of derivatives 196, 197 and 198 197 and 198 that inhibits Candida albicans was synthesized [128]. 1,2-Dioxene 196а showed high that inhibits Candida albicans was synthesized [128]. 1,2-Dioxene 196a showed high antifungal activity antifungal activity against C. tropicalis and C. krusei [129]. against C. tropicalis and C. krusei [129].

SchemeScheme 32. 32.Synthesis Synthesis ofof 1,2-dioxenes1,2-dioxenes 196 andand their their further further modification. modification.

6. 1,2,4-Trioxanes6. 1,2,4-Trioxanes AmongAmong the the class class of of 1,2,4-trioxane,1,2,4-trioxane, various various aspects aspects of ofthe the biological biological activity activity of artemisinin of artemisinin and its and itsderivatives derivatives are are studied studied most most extensextensively.ively. Synthetic Synthetic strategies strategies for peroxide for peroxide ring ringconstruction construction in inartemisinin artemisinin were were discussed discussed in in detail detail [130]. [130]. Compared Compared with with other other methods methods the the synthesis synthesis of of artemisininartemisinin (1 ()1)based based onon dihydroartemisinic acid acid seems seems most most preferable preferable [131], [131 as], it ascan it satisfy can satisfy the thedemand demand for for cheaper cheaper production production of sufficient of sufficient quan quantitiestities of artemisinin. of artemisinin. The key The stages key stagesof the of thetransformation transformation of of dihydroartemisinic dihydroartemisinic acid acid into into artemisinin artemisinin (1) ( 1are) are described described in inthe the fundamental fundamental studies of Richard K. Haynes [132]. studiesstudies of of Richard Richard K. K. Haynes Haynes [132 [132].].

Molecules 2017, 22, 1881 21 of 39 Molecules 2017, 22, 1881 21 of 39 Molecules 2017, 22, 1881 21 of 39 InIn addition addition toto antimalarialantimalarial andand cytotoxiccytotoxic activity, artemisinin artemisinin (1 (1) )has has activity activity against against trypanosomatidestrypanosomatidesIn additionLeishmania Leishmaniato antimalarial major major[ 133 and[133],], Leishmaniacytotoxic Leishmania activity, donovani donovani [artemisinin134 [134],], Trypanosoma Trypanosoma (1) has brucei activitybrucei rhodesiense rhodesiense againstand Trypanosomaandtrypanosomatides Trypanosoma cruzi [ 135cruzi Leishmania], as[135], well asmajor as well parasite [133], as parasite ToxoplasmaLeishmania Toxoplasma donovani gondii (Scheme gondii [134], (SchemeTrypanosoma 33) [136 33)]. Artemisinin [136].brucei Artemisininrhodesiense showed a synergisticshowedand Trypanosoma a synergistic or additive cruzi or effect [135], additive in as combination well effect as inparasite combination with itraconazoleToxoplasma with gondii againstitraconazole (Scheme fungi againstAspergillus 33) [136]. fungi fumigatusArtemisinin Aspergillus[137 ], asfumigatus wellshowed as moderate a[137], synergistic as activitywell or as additive againstmoderate Fusariumeffect activity in combination oxysporum against Fusarium[ 138with]. Antiviralitraconazole oxysporum activity [138]. against ofAntiviral artemisininfungi Aspergillus activity (1) wasof reportedartemisininfumigatus in few[137], (1)studies; was as reportedwell inhibition as moderate in few of studies; the activity inhibition against immunodeficiency Fusariumof the human oxysporum virusimmunodeficiency (HIV-1)[138]. Antiviral at 60% virus inactivity peripheral (HIV-1) of artemisinin (1) was reported in few studies; inhibition of the human immunodeficiency virus (HIV-1) bloodat 60% mononuclear in peripheral cells [139 mononuclear], the hepatitis cells C virus[139], (HCV)the hepatitis in human C virus liver (HCV) cells [in140 human], the bovine liver cells viral at 60% in peripheral blood mononuclear cells [139], the hepatitis C virus (HCV) in human liver cells diarrhea[140], the virus bovine (BVDV) viral diarrhea [141], as virus well as(BVDV) hepatitis [141 B], virusas well [142 as hepatitis] was shown. B virus [142] was shown. [140], the bovine viral diarrhea virus (BVDV) [141], as well as hepatitis B virus [142] was shown.

H L. major in vitro H T. gondii complete elimination O promastigotesL. major in vitro ED50 = 0.75 M T.at gondii1.3 g/mLcomplete for 14 elimination days OO amastigotespromastigotes ED ED= 30= 0.75 M M at 1.3 g/mL for 14 days O 50 50 O amastigotes ED = 30 M O H 50 A. fumigatus MIC50 = 125 g/mL H O L. donovani in vitro A.F. fumigatusoxysporumMIC inhibition= 125 72% g/mL at H H 50 O promastigotesL. donovani in vitro IC50 = 160 M F.200 oxysporum g/mL inhibition 72% at O amastigotespromastigotes IC 50 IC=50 22= 160 M M 200 g/mL O artemisinin (1) amastigotes IC50 = 22 M HIV-1 60% inhibition 10 M T. cruzi IC50 = 13.4 M artemisinin (1) HIV-1HCV EC60%50 inhibition= 78 M 10 M T.T. bruceicruzi IC rhodesiense50 = 13.4 MIC = 20.4 M 50 HCVBVDV EC 60%50 = inhibition78 M 100 M T. brucei rhodesiense IC = 20.4 M 50 BVDV 60% inhibition 100 M SchemeScheme 33. 33.Artemisinin Artemisinin and various types types of of its its bioactivity. bioactivity. Scheme 33. Artemisinin and various types of its bioactivity. Artemisinin derivative, artemether (3), is actively used to treat schistosomiasis, a parasitic ArtemisininArtemisinin derivative, derivative, artemether artemether (3 ),(3 is), activelyis actively used used to treat to trea schistosomiasis,t schistosomiasis, a parasitic a parasitic disease disease caused by flat of the genus Schistosomiasis [46,47]. A double-blind field trial in the causeddisease by flatcaused worms by flat of theworms genus ofSchistosomiasis the genus Schistosomiasis[46,47]. A double-blind[46,47]. A double-blind field trial infield the trial Poyang in the Lake Poyang Lake region (southern China) confirmed that artemether (3) significantly reduces the regionPoyang (southern Lake China)region confirmed(southern thatChina) artemether confirmed (3 )that significantly artemether reduces (3) significantly the frequency reduces and intensity the frequency and intensity of S. japonicum infection and does not cause side effects [143]. Despite the of S.frequency japonicum andinfection intensity and of S. does japonicum not cause infection side effects and does [143 not]. Despite cause side the effects proven [143]. pathogenic Despite effectsthe proven pathogenic effects on the reproductive system of Fasciola hepatica [144,145], artemether (3) onproven the reproductive pathogenic systemeffects on of Fasciolathe reproductive hepatica [ 144system,145 ],of artemetherFasciola hepatica (3) had [144,145], practically artemether no effect (3) in had practically no effect in the treatment of fascioliasis in [146]. Artemether activity against thehad treatment practically of fascioliasisno effect in the in treatment humans [of146 fascioliasis]. Artemether in humans activity [146]. against ArtemetherLeishmania activity major against[133 ], Leishmania major [133], and Toxoplasma gondii [136,147] was detected; it was shown also that andLeishmaniaToxoplasma major gondii [133],[136 and,147 Toxoplasma] was detected; gondii it[136,147] was shown was detected; also that it artemether was shown is also effective that in artemether is effective in the treatment of experimental rheumatoid arthritis [148,149]. Artemether theartemether treatment ofis experimentaleffective in the rheumatoid treatment of arthritis experimental [148,149 rheumatoid]. Artemether arthritis (3) is obtained[148,149]. byArtemether reduction of (3) is obtained by reduction of artemisinin (1) to dihydroartemisinin (2) followed by methylation artemisinin(3) is obtained (1) to dihydroartemisininby reduction of artemisinin (2) followed (1) to by dihydroartemisinin methylation (Scheme (2) 34followed)[150,151 by]. methylation This synthesis (Scheme 34) [150,151]. This synthesis can be performed in flow reactor [152,153]. can(Scheme be performed 34) [150,151]. in flow This reactor synthesis [152, 153can]. be performed in flow reactor [152,153].

SchemeSchemeScheme 34. 34.Synthesis SynthesisSynthesis of artemether (( (333)) ) andand and itsits its bioactivity.bioactivity. bioactivity.

ArtesunateArtesunateArtesunate ( 4 ((),44),), artemisinin artemisininartemisinin derivative derivativederivative containingcontaining freefree free carboxyliccarboxylic carboxylic groupgroup group showed showed showed high high high efficiency efficiency efficiency againstagainstagainstS. S.S. japonicum japonicumjaponicum [ [154,155],154[154,155],,155], and and also also in in the the therapy therapy ofof offascioliasisfascioliasis fascioliasis causedcaused caused byby FasciolaFasciola by Fasciola hepatica hepatica hepatica or or orFasciolaFasciola giganticagigantica gigantica (Scheme(Scheme(Scheme 35)35) 35 [156].[156].)[156 It]. was It was determined determined thatthat thatartesunateartesunate artesunate ((44)) causescauses (4) causes changeschanges changes in in the the in reproductive system of Fasciola hepatica [144]. Antiviral activity of artesunate is displayed against the thereproductive reproductive system system of Fasciola of Fasciola hepatica hepatica [144]. Antiviral[144]. Antiviral activity of activity artesunate of is artesunate displayed isagainst displayed the

Molecules 2017, 22, 1881 22 of 39 Molecules 20172017,, 2222,, 18811881 2222 ofof 3939 againsthepatitis the В virusvirus hepatitis [157][157] B andand virus thethe [157 hepatitishepatitis] and the CC hepatitisvirusvirus [158],[158], C virusthethe herpesherpes [158], virusvirus the herpes (HHV)(HHV) virus typetype (HHV) 44 andand typetype 466 and[159,160],[159,160], type 6 [humanhuman159,160 ],cytomegaloviruscytomegalovirus human cytomegalovirus (HCMV)(HCMV) (HCMV) [16[161–163], [161 –including163], including therapy-resistant therapy-resistant mutants mutants of ofhuman human cytomegalovirus cytomegalovirus [164]. [164 ].Artesunate Artesunate (4 ())4 is)is is preparedprepared prepared byby by reactionreaction reaction ofof of dihydroartemisinindihydroartemisinin dihydroartemisinin ( (2)) with with succinicsuccinic anhydrideanhydride inin basicbasic conditionscoconditions (Scheme(Scheme 3535))[ [152].152].

Scheme 35. SynthesisSynthesis of of artesunate artesunate ( (44)) and and its its bioactivity. bioactivity.

TheThe librarylibrary ofof 10-deoxo-derivativies10-deoxo-derivativies of artemisininartemisinin 205 showedshowed highhigh activityactivity againstagainstagainst parasitesparasitesparasites LeishmaniaLeishmania donovani (Scheme(Scheme 36).3636).). SynthesisSynthesis ofof 205 waswas performed performed from from artemisitene 199 byby radicalradical additionaddition ofof compoundcompound 200200 followedfollowedfollowed bybyby reductionreductionreduction ofofof carbonylcarbonylcarbonyl groupgroupgroup ininin 202 202... DehydrationDehydrationDehydration andand deprotectiondeprotection resulted in phenolphenol 204204,, whichwhich formedformed a a seriesseries ofof compoundscompounds 205 byby reactionreaction withwith derivativesderivatives ofof carboxyliccarboxylic andand sulfonicsulfonic acidsacids [[165].165].

H H O O OTIPS O O OTIPS O [(CH[(CH33))33Si]Si]33 SiHSiH O H H AIBN,AIBN, CC66H66 H H H O BrBr H O 63%63% O 199199 O 200200 201201 H H O O O OTIPS O OTIPS DBU O DIBAL-H O THFTHF H THFTHF H H O H O 50%50% 85%85% O OH 202202 203203 H 1)1) EtEt SiH,SiH, BFBF OEt RCOCl/RSO Cl/RNCO or thiophosgene 33 33 22 O 22 CH2Cl2 EtEt3N 2 2 O OH 3 2)2) pyridinepyridine O CH22Cl22 H 3)3) TBAF,TBAF, THFTHF H O 6060 98%98% 72%72% R == RCO-,RCO-, RSORSO -,-, RNHCO-RNHCO- 204204 11 22 R = Alk, Ar H O O OR O 11 L.L. donovanidonovani H IC = 0.26 - 3.18 M H O IC5050 = 0.26 - 3.18 M

205205 SchemeScheme 36.36. AntileishmaniasisAntileishmaniasis derivatives ofof artemisininartemisinin 205205..

Molecules 2017, 22, 1881 23 of 39 Molecules 2017, 22, 1881 23 of 39

Attempts to synthesize the antitoxoplasma deriva derivativestives of artemisinin have been made [147,166], [147,166], however their inin vitrovitro activityactivity diddid notnot exceedexceed thethe activityactivity ofof artemetherartemether ((33).). Among artemisininartemisinin derivatives derivatives tested tested for for fungicidal fungicidal activity, activity, anhydrodihydroartemisinin anhydrodihydroartemisinin (206 )(206 and) arteetherand arteether (207) ( were207) were most activemost active against againstCryptoccocus Cryptoccocus neoformans neoformans[167], their [167], activity their activity surpassed surpassed the one ofthe amphotericin one of . Both derivatives B. Both were derivatives obtained [168were,169 ]obtained in one step [168,169] from dihydroartemisinin in one step from (2) (Schemedihydroartemisinin 37). Later it ( was2) (Scheme found that37). arteetherLater it was (207 found)[170] that exhibits arteether moderate (207) antiviral[170] exhibits activity moderate against humanantiviral immunodeficiency activity against human virus and immunodefici anhydrodihydroartemisininency virus and anhydrodihydroartemisinin (206)[171] is high active against (206) hepatitis[171] is high B virus. active against hepatitis B virus.

H O C. neoformans BF OEt O IC50 = 0.045 g/mL BF3 OEt2 O H Et2O H HBV IC = 0.1 M H O HBV IC50 = 0.1 M 85% O anhydrodihydroartemisinin (206) O O H H H O O O EtOH O C. neoformans OH BF OEt 3 2 O IC50 = 0.085 g/mL H H 2 PhCH3 H O HIV-1 IC = 30.9 M 72% 50 O

207 arteether (207)

Scheme 37. Antifungal and antiviral artemisinin derivatives— a anhydrodihydroartemisininnhydrodihydroartemisinin (206)) and arteether (207).).

High antiviral activity against human immunodeficiencyimmunodeficiency virus [170] [170] was demonstrateddemonstrated by butyl-derivative of artemisinin 209, prepared via photo-oxidationphoto-oxidation of alcohol 208 with 12% yield (Scheme(Scheme 3838))[ [172].172].

Scheme 38. Antiviral artemisinin derivative 209..

Combination of dihydroartemisinin ( 2) with antiviral drugdrug azidothymidineazidothymidine ( 210) resultedresulted inin compound 211 exhibited both antimalarial asas antiviralantiviral activityactivity (Scheme(Scheme 3939))[ [173].173]. A new trend in the medical chemistry of artemisi artemisininnin derivatives is the synthesissynthesis of dimers and trimers.trimers. AmongAmong aa series series of of artemisinin artemisinin dimers dimers obtained obtained by condensationby condensation of dihydroartemisinin of dihydroartemisinin (2) with (2) binucleophile,with binucleophile, compounds compounds212 and 212213 andshowed 213 showed the highest theactivity highest against activity fungi againstCryptococcus fungi Cryptococcus neoformans andneoformans parasites andLeishmania parasites donovani, Leishmaniarespectively donovani, (Schemerespectively 40) [ (Scheme174]. 40) [174].

Molecules 2017, 22, 1881 24 of 39 Molecules 2017, 22, 1881 24 of 39 MoleculesMolecules 2017 2017, 22,, 188122, 1881 24 of 3924 of 39 Molecules 2017, 22, 1881 24 of 39

SchemeSchemeSchemeScheme 39. 39.Synthesis 39. Synthesis39. Synthesis Synthesis of of hybrid hybridof of hybrid hybrid211 211 based 211 based211 based based onon dihydroartemisinin on on dihydroartemisinin dihydroartemisinin 22 andand 2 2 azidothymidineand and azidothymidine azidothymidine azidothymidine 210210. 210 .210. . Scheme 39. Synthesis of hybrid 211 based on dihydroartemisinin 2 and azidothymidine 210.

Scheme 40. Synthesis of artemisinin dimers 212 and 213 with antifungal and anti-parasitic activity. SchemeSchemeSchemeScheme 40. 40.Synthesis 40. Synthesis40. Synthesis Synthesis of of artemisinin artemisininof of artemisinin artemisinin dimersdimers dimers dimers 212 212and 212 and 213213and with213 with213 with withantifungal antifungal antifungal antifungal and and anand and anti-parasiticti-parasitic an anti-parasiticti-parasitic activity. activity. activity. activity. Dimers and trimers of artemisinin showed antiviral activity were summarized in Table 1. DimersDimersDimers and and and trimers trimers trimers of artemisininof of artemisinin artemisinin showed showed showed anti anti viralantiviralviral activity activity activity were were were summarized su summarizedmmarized in Table in in Table Table 1. 1. 1. Dimers and trimersTable of 1. artemisinin Dimers and trimers showed of artemisi antiviralnin activity showed wereantiviral summarized activity. in Table1. TableTableTable 1. Dimers 1. 1. Dimers Dimers and and andtrimers trimers trimers of artemisi of of artemisi artemisinin showedninnin showed showed antiviral antiviral antiviral activity. activity. activity. Dimer/Trimer No. Table 1. Dimers and trimers of artemisininSynthesis showed antiviral activity.Bioactivity DimerDimerStructureDimer/Trimer/Trimer/Trimer No.No.No. SynthesisSynthesisSynthesis BioactivityBioactivityBioactivity No. Dimer/TrimerStructureStructureStructure Structure Synthesis Bioactivity

from artemisinin (1) 3 HCMV EC50 = 0.15 µM 1 50 fromsteps, artemisinin 67% [175] (1 ) 3 HCMV[176,177] EC = 0.1550 µM 1 fromfromfrom artemisinin artemisinin (1) ( (11)) 3 3 HCMVHCMVHCMVEC50 EC =EC 0.1550 = =µ 0.15 M0.15 µM µM 1 11 steps, 67% [175] [176,177] 3steps, steps,steps, 67% 67% 67% [175 [175] [175]] [176,[176,177]177[176,177]] 214 214 214214214

from 214 3 steps, 42% HCMV EC50 = 0.06 µM 2 from 214 3 steps, 42% HCMV EC50 = 0.06 µM from[178]214 3 steps, [176] 50 22 fromfrom 214 214 3 3 steps, steps, 42% 42% HCMVHCMVHCMVEC = 0.06EC ECµ50 M[= = 0.06 0.06176] µM µM 22 [178]42% [178 ] 50[176] [178][178] [176][176] 215 215215 215215

Molecules 2017, 22, 1881 25 of 39

Table 1. Cont. MoleculesMolecules 20172017,, 2222,, 18811881 2525 ofof 3939 Molecules 2017,, 22,, 18811881 25 of 39 No. Dimer/Trimer Structure Synthesis Bioactivity ARTART ARTART

OO HCMVHCMV ECEC5050 == 0.040.04 µMµM from 214 1 step, HCMVHCMVEC50 ECEC= 0.045050 ==µ 0.040.04M µMµM 3 33 PP fromfrom 214214 11 step,step, 96%96% [179][179] 3 OO P OO from 21496% 1 [step,179] 96% [179] [180–[180–182][180–182]182] O OOO [180–182] O PhPh PhPh Ph Ph 216216

from 214 1 step, HCMVHCMV ECEC5050 == 4444 nMnM 4 44 fromfrom 214214 11 step,step, 25%25% [183][183]HCMV HCMVEC = 44EC nM50 = [183 44] nM 4 from 21421425% 11 [step,step,183] 25%25% [183][183] 50 [183][183]

217217

fromfromfromthreo threothreo-214--214214and andandand HCMVHCMVHCMVEC50 ECEC= 0.045050 ==µ 0.04M0.04 µMµM 5 5 artesunate (4), ( 14), step, 1 step, HCMV ECEC50 == 0.040.04 µMµM 5 artesunate (4), 1 step, [184,185] quantitative yield [184] [184,185][184,185] quantitativequantitative yieldyield [184][184]

218 218218

fromfromfrom threothreothreo--214214 1 11 step, step,step, 67%67% HCMVHCMV ECEC5050 == 0.110.11 µMµM 6 from threo-214 11 step,step, 67%67%HCMV HCMVEC = 0.11ECEC5050µ M[== 0.110.11186] µMµM 66 67% [186] 50 [186][186] [186][186]

219 219219

HCVHCV ECEC5050 == 3.23.2 µMµM 7 not reported HCV ECHCV50 = EC 3.2ECµ50M[ == 3.21873.2] µMµM 77 notnot reportedreported [187][187]

220 220220

SyntheticSyntheticSynthetic 1,2,4-trioxanes 1,2,4-trioxanes1,2,4-trioxanes223 223obtained223 obtainedobtainedobtained by condensationbybyby condensationcondensationcondensation of hydroxy-hydroperoxideofofof hydroxy-hydroperoxidehydroxy-hydroperoxidehydroxy-hydroperoxide221 221221with withwithwith adamantaneadamantaneadamantane followed followedfollowed by hydrolysisbyby hydrolysishydrolysis of esterofof esterester222 222222showed showedshowedshowed high highhighhighin vivoininin vivovivovivoactivity activityactivityactivity against againstagainstagainst helminths helminthshelminthshelminths FasciolaFasciolaFasciola hepatica hepaticahepaticain rats ininin (Schemeratsratsrats (Scheme(Scheme(Scheme 41)[ 41)41)18841) [188].].[188].[188].

Molecules 2017, 22, 1881 26 of 39 Molecules 2017, 22, 1881 26 of 39 Molecules 2017, 22, 1881 26 of 39

Scheme 41. Anthelminthic activity of synthetic 1,2,4-trioxanes 223. Scheme 41. Anthelminthic activity of synthetic 1,2,4-trioxanes 223. Scheme 41. Anthelminthic activity of synthetic 1,2,4-trioxanes 223. 7. 1,2,4,5-Tetraoxanes 7. 1,2,4,5-Tetraoxanes Synthetic 1,2,4,5-tetraoxane 226 [189], prepared by condensation of bis-hydroperoxide 224 with Synthetic 1,2,4,5-tetraoxane 226 [189],[189], prepared by condensation of bis-hydroperoxide 224 with adamantanone followed by hydrolysis ester 225, showed high in vivo activity against helminths adamantanone followed by hydrolysis ester 225,, showed showed high high inin vivovivo activityactivity against helminths Fasciola hepatica in rats (Scheme 42) [188]. Fasciola hepatica inin ratsrats (Scheme(Scheme 4242))[ [188].188]. HOO OOH HOO OOH O O O HOO OOH HBF4 O O O HBF4 O O O EtOAcHBF EtOAc4 OO CO2Et EtOAc50% OO CO2Et 50% 224 OO225 CO2Et 224 CO2Et 50% 225 224 CO2Et 225 KOH CO2Et KOH CH3OH O O CHKOH3OH O O 100% worm burden reduction 100% worm burden reduction CH3OH O O 87% OO CO H 100%F. hepatica worm inburden rats at reduction 50 mg/kg 87% OO CO2H F. hepatica in rats at 50 mg/kg 87% 2 F. hepatica in rats at 50 mg/kg OO226 CO2H 226 226 Scheme 42. Synthesis of 1,2,4,5-tetraoxane 226 with high anthelmintic activity. Scheme 42. Synthesis of 1,2,4,5-tetraoxane 226 with high anthelmintic activity. Scheme 42. Synthesis of 1,2,4,5-tetraoxane 226 with high anthelmintic activity. Based on related 1,2,4,5-tetraoxanes 227,, hybrids 229 with a fragment of an anthelmintic Based on related 1,2,4,5-tetraoxanes 227, hybrids 229 with a fragment of an anthelmintic drug 228 were obtained (Scheme 4343))[ [190].190]. Synthesized Synthesized hybrids hybrids 229229 exhibit high activity praziquantel 228 were obtained (Scheme 43) [190]. Synthesized hybrids 229 exhibit high activity against Schistosoma japonicum and Schistosoma mansonimansoni [[191].191]. against Schistosoma japonicum and Schistosoma mansoni [191].

NH2 NH2 NH O O O 2 O O O O O EDCl R EDCl R O O O O OO OH N pyridineEDCl R OO OH N pyridine N pyridine OO OH N N 227 N 227 228 O 227 228 O 228 O O O O O O O R R O O O OO NH R OO NH worm burden reduction OO NH worm burden reduction O adultworm and burdenjuvenile reduction S.japonicum O adult and juvenile S.japonicum 229aadultR = and adamantyl juvenile upS.japonicum to 42% O 229a R = adamantyl up to 42% N 229b R = cyclopentyl up to 35% N 229b229a R = adamantylcyclopentyl up up to to 42% 35% N N 229c R = dimethyl up to 25% 229 N 229c229b R = dimethylcyclopentyl up upto 25%to 35% 229 N 229c R = dimethyl up to 25% 229 O O O Scheme 43. Synthesis of hybrids 229 as anti-schistosomal agents. Scheme 43. Synthesis of hybrids 229 as anti-schistosomal agents. Scheme 43. Synthesis of hybrids 229 as anti-schistosomal agents.

Molecules 2017, 22, 1881 27 of 39 Molecules 2017, 22, 1881 27 of 39 MoleculesBridged 2017, 22 1,2,4,5-tetraoxanes, 1881 231 demonstrated high in vitro and in vivo activity against27 of 39 trematodes Schistosoma mansoni [74,192]. The best result was shown for adamantane-substituted Bridged 1,2,4,5-tetraoxanes 231 demonstrated high in vitro and in vivo activity against tetraoxaneBridged 231a 1,2,4,5-tetraoxanes which caused231 75%demonstrated worm burden high inreductions vitro and in vivoS. mansoniactivity againstharbored trematodes in mice trematodes Schistosoma mansoni [74,192]. The best result was shown for adamantane-substituted Schistosomafollowing the mansoni administration[74,192]. The of bestperoxide result at was single shown oral for dose adamantane-substituted of 400 mg/kg. Peroxides tetraoxane 231 were231a tetraoxane 231a which caused 75% worm burden reductions in S. mansoni harbored in mice whichsynthesized caused from 75% β worm-diketones burden 230 reductions and H2O in2 withS. mansoni good yieldsharbored by inthe mice action following of various the administrationacids: sulfuric following the administration of peroxide at single oral dose of 400 mg/kg. Peroxides 231 were of[193], peroxide phosphomolybdic at single oral and dose phosphot of 400 mg/kg.ungstic Peroxidesacids [194]231 (Schemewere synthesized 44). from β-diketones 230 synthesized from β-diketones 230 and H2O2 with good yields by the action of various acids: sulfuric and H2O2 with good yields by the action of various acids: sulfuric [193], phosphomolybdic and phosphotungstic[193], phosphomolybdic acids [194 and] (Scheme phosphot 44ungstic). acids [194] (Scheme 44). O O O O O O O O O O O O H2O2 O O O O H2SO4 or O O 231a H2O2 R PMA or PWA O OR in vitro H SO or 230 412 83%4 231 adult S. mansoni231a IC50 = 0.3 M R PMA or PWA R NTSin vitro S. mansoni IC50 = 0.1 M 230 41 83% 231 inadult vivo S. mansoni IC50 = 0.3 M NTS S. mansoni IC = 0.1 M 75% worm burden reduction50 in vivo Scheme 44. Synthesis of bridged 1,2,4,5-tetraoxanes75% worm burden 231. reduction Scheme 44. Synthesis of bridged 1,2,4,5-tetraoxanes 231. 8. Acyclic Peroxides Scheme 44. Synthesis of bridged 1,2,4,5-tetraoxanes 231.

8. AcyclicMany Peroxides acyclic peroxides are applied as oxidants in organic synthesis [195,196]. Benzoyl peroxide (234) is actively used in the food industry as a flour bleach [197–199], and in pharmaceuticals. The Many acyclicacyclic peroxides peroxides are are applied applied as as oxidants oxidants in organicin organic synthesis synthesis [195 [195,196].,196]. Benzoyl Benzoyl peroxide peroxide (234) first mention about the medical using of benzoyl peroxide dates back to 1929, where Lyon and is(234 actively) is actively used inused the in food the industryfood industry as a flouras a fl bleachour bleach [197– 199[197–199],], and inand pharmaceuticals. in pharmaceuticals. The firstThe Reynolds reported effective treatment of burns, wounds and varicose veins by benzoyl peroxide mentionfirst mentionabout about the medical the medical using ofus benzoyling of benzoyl peroxide peroxide dates back dates to 1929,back whereto 1929, Lyon where and Lyon Reynolds and [200]. Subsequently it was found that it has antibacterial [201,202], anti-inflammatory [203], reportedReynolds effectivereported treatmenteffective trea oftment burns, of wounds burns, wounds and varicose and vari veinscose byveins benzoyl by benzoyl peroxide peroxide [200]. cheratolic [204], and wound-healing [205,206] effects. Presently, benzoyl peroxide is widely used Subsequently[200]. Subsequently it wasfound it was that found it has antibacterialthat it has [antibacterial201,202], anti-inflammatory [201,202], anti-inflammatory [203], cheratolic [203], [204], agent for acne treatment because of its efficacy and good tolerability in patients [207,208]. Benzoyl andcheratolic wound-healing [204], and [wound-healing205,206] effects. [205,206] Presently, effects. benzoyl Presently, peroxide benzoyl is widely peroxide used is agent widely for used acne peroxide is a good alternative to monotherapy with for the treatment of Acne vulgaris treatmentagent for becauseacne treatment of its efficacy because and of good its efficacy tolerability and ingood patients tolerability [207,208 in]. patients Benzoyl [207,208]. peroxide isBenzoyl a good caused antibiotic-resistant strains, for example Propionibacterium acnes [209,210]. alternativeperoxide is to a monotherapygood alternative with to antibiotics monotherapy for the with treatment antibiotics of Acne for vulgaris the treatmentcaused antibiotic-resistant of Acne vulgaris Benzoyl peroxide is commercially produced by the reaction of benzoyl chloride (232), sodium strains,caused antibiotic-resistant for example Propionibacterium strains, for acnesexample[209 Propionibacterium,210]. acnes [209,210]. hydroxide and hydrogen peroxide (Scheme 45, top) [211,212]. Benzoyl peroxide can also be prepared Benzoyl peroxide peroxide is commerciallyis commercially produced produced by the by reaction the reaction of benzoyl of benzoyl chloride (chloride232), sodium (232 hydroxide), sodium from benzoic anhydride (233) by the action of an alkali metal perborate in an aqueous solution andhydroxide hydrogen and peroxide hydrogen (Scheme peroxide 45, (Scheme top) [211 ,45,212 top)]. Benzoyl [211,212]. peroxide Benzoyl can peroxi also bede prepared can also from be prepared benzoic (Scheme 45, bottom) [213]. anhydridefrom benzoic (233 )anhydride by the action (233 of) an by alkali the metalaction perborate of an alkali in an metal aqueous perborate solution (Schemein an aqueous 45, bottom) solution [213]. (Scheme 45, bottom) [213].

Scheme 45. Benzoyl peroxide (234) production. Scheme 45. Benzoyl peroxide (234) production.

Oxanthromicin ( 235) isolatedScheme from45. Benzoyl bacteria peroxide Actinomadura (234) production. sp. [[214]214 ] showedshowed highhigh antifungalantifungal activity against Trichophyton mentagrophytes,, Micosporum canis, M. gypseum , Epidermophyton floccosum floccosum,, Oxanthromicin (235) isolated from bacteria Actinomadura sp. [214] showed high antifungal Candida albicans,, andand Aspergillus nigerniger (Scheme(Scheme 4646))[ [215].215]. activity against Trichophyton mentagrophytes, Micosporum canis, M. gypseum, Epidermophyton floccosum, Candida albicans, and Aspergillus niger (Scheme 46) [215].

Molecules 2017, 22, 1881 28 of 39 Molecules 2017, 22, 1881 28 of 39 Molecules 2017,, 22,, 18811881 28 of 39 OH O OH O COOH COOH MIC ( g/mL) Trichophyton mentagrophytes MIC 4( g/mL) OH TrichophytonMicosporum canismentagrophytes 44 O OH Micosporum canis 4 O M. gypseum 2 O M.Epidermophyton gypseum floccosum 28 O OH Epidermophyton floccosum 8 OH EpidermophytonCandida albicans floccosum 88 CandidaAspergillus albicans niger 88 COOH Aspergillus niger 8 COOH OH O OH O Oxantromicin (235) Oxantromicin (235) Oxantromicin ( ) Scheme 46. Antifungal natural acyclic peroxide, oxanthromicin ((235235).). Scheme 46. AntifungalAntifungal naturalnatural acyclicacyclic peroxide,peroxide, oxanthromicinoxanthromicin ((235). Hydroperoxide 236 obtained by biotransformation of Artemisia cina metabolites exhibits high in Hydroperoxide 236236 obtainedobtained by by biotransformation biotransformation of of ArtemisiaArtemisia cina cina metabolitesmetabolites exhibits exhibits high high in vitroHydroperoxide activity against 236 obtained Trypanosoma by biotransformation brucei (Scheme of Artemisia 47) [216]. cina metabolites exhibits high in vitroin vitro activity activity against against protozoa protozoa TrypanosomaTrypanosoma brucei brucei (Scheme(Scheme 47) 47 [216].)[216 ].

H H O O H O O H O O O OH O OH O OH 236 O 236 Tripanosoma brucei EC ( g/mL) 0.40 Tripanosoma brucei EC50 ( g/mL) 0.40 Tripanosoma brucei EC50 ( g/mL) 0.40 Scheme 47. Anti-trypanosomal hydroperoxide 236. Scheme 47. Anti-trypanosomalAnti-trypanosomal hydroperoxidehydroperoxide 236.. Four monoterpene hydroperoxides 237a–d were isolated from aerial parts of Chenopodium Four monoterpene hydroperoxides 237a–d were isolated from aerial parts of Chenopodium ambrosioidesFour monoterpenemonoterpene. Minimum hydroperoxides lethal hydroperoxides concentration237a 237a–d (MLC)were–d wereisolated in vitro isolated from of its aerial peroxidesfrom parts aerial ofagainstChenopodium parts Trypanosoma of Chenopodium ambrosioides cruzi. ambrosioides. Minimum lethal concentration (MLC) in vitro of its peroxides against Trypanosoma cruzi ambrosioidesMinimumwas 1.2, 1.6, lethal. 3.1,Minimum and concentration 0.8 lethal µM, respectivelyconcentration (MLC) in vitro (Scheme (MLC)of its 48)in peroxides vitro [107]. of its against peroxidesTrypanosoma against Trypanosoma cruzi was 1.2, cruzi 1.6, was 1.2, 1.6, 3.1, and 0.8 µM, respectively (Scheme 48) [107]. was3.1, and1.2, 0.81.6,µ 3.1,M, respectivelyand 0.8 µM, (Scheme respectively 48) [107 (Scheme]. 48) [107]. OOH HOO HOO HOO OOH HOO HOO HOO

237a 237b 237c 237d 237a 237b 237c 237d Tripanosoma cruzi MLC ( M) 1.2 Tripanosoma 1.6 cruzi 3.1MLC ( M) 0.8 1.2 1.6 3.1 0.8 1.2 1.6 3.1 0.8 Scheme 48. Hydroperoxides 237a–d isolated from Chenopodium ambrosioides. SchemeScheme 48. HydroperoxidesHydroperoxidesHydroperoxides 237a237a––d isolatedisolated fromfrom Chenopodium ambrosioides .. A geminal bis-hydroperoxides 239 synthesized from cyclic ketones 238 show pronounced in A geminal bis-hydroperoxides 239 synthesized from cyclic ketones 238 show pronounced in vitroA geminalgeminal bisbis-hydroperoxides -hydroperoxidesand antifungal activity239 239synthesized synthesized against B. from cereusfrom cyclic , cyclicE. coli ketones ,ketones P. aeruginosa238 238show show, S. pronounced aureus pronounced, C. albicansin vitro in, vitro antimicrobial and antifungal activity against B. cereus, E. coli, P. aeruginosa, S. aureus, C. albicans, vitroantimicrobialand A.antimicrobial niger comparable and antifungaland antifungal with activity the activity effect against againstof someB. cereusB. cereusantiseptics, E., E. coli coli, and,P., P. aeruginosa aeruginosa to a lesser, ,S. S. aureusextent,aureus,, C.antibiotics albicans albicans,, and A. niger comparable with the effect of some antiseptics and, to a lesser extent, antibiotics and(Scheme A. niger 49) [217]. comparable with the effect of some antiseptics and, to a lesser extent, antibiotics (Scheme 49)49)[ [217].217].

Molecules 2017, 22, 1881 29 of 39 Molecules 2017, 22, 1881 29 of 39

Scheme 49. Antimicrobial and antifungal geminal bis-hydroperoxides 239..

9. Conclusions The biologicalbiological activity activity of organicof organic peroxides peroxides is usually is usually associated associated with the with antimalarial the antimalarial properties ofproperties artemisinin of artemisinin and its derivatives. and its derivatives. However, However, the analysis the ofanalysis published of published data indicates data indicates that organic that peroxidesorganic peroxides exhibit a varietyexhibit ofa biologicalvariety of activity—anthelmintic, biological activity—anthelmintic, antifungal, antiviral, antifungal, etc.—which antiviral, is stilletc.—which being given is still insufficient being given attention. insufficient attention. Efforts ofof synthetic synthetic chemists chemists are are currently currently directed directed at the at development the development of methods of methods for the synthesis for the ofsynthesis biologically of biologically active natural active peroxides, natural peroxides, the modification the modificati of naturalon of peroxides natural peroxides and the search and the of syntheticsearch of synthetic peroxides, peroxides, which are which not are inferior not inferi to theiror to naturaltheir natural and semisynthetic and semisynthetic analogs, analogs, but but are substantiallyare substantially cheaper. cheaper. It seems It seems that that progress progress in the in the synthesis synthesis ofbiologically of biologically active active peroxides peroxides will will be mainlybe mainly related related to theto the last last two two directions. directions. In view of very dynamic development of of these these ar areaseas of of medical chemistry, chemistry, in the near future, one shouldshould expect expect a breakthrough a breakthrough in the in synthesis the synthe of biologicallysis of biologically active peroxides active and peroxides in understanding and in ofunderstanding its action with of respectits action to awith wide resp rangeect to of a bio-targets. wide range of bio-targets.

Acknowledgments: TheThe authors authors are are grateful grateful toto the the Russian Russian Science Science Foundation Foundation (Grant (Grant 17-73-10364) 17-73-10364) for the for the financial support. financial support. Author Contributions: All authors have contributed substantially: V.A.V., I.A.Y., I.A.I. and A.O.T. wrote theAuthor manuscript; Contributions: and V.A.V. All andauthors I.A.Y. have researched contributed the literature substantially: and wrote V.A.V., the I.A.Y., manuscript. I.A.I. and A.O.T. wrote the manuscript; and V.A.V. and I.A.Y. researched the literature and wrote the manuscript. Conflicts of Interest: The authors declare no conflict of interest. Conflicts of Interest: The authors declare no conflict of interest. References References 1. Patnaik, P. Peroxides, organic. In A Comprehensive Guide to the Hazardous Properties of Chemical Substances; 1. Patnaik,John Wiley P. &Peroxides, Sons, Inc.: organic. Hoboken, In A NJ, Comprehensive USA, 2006; pp. Guide 719–740. to the Hazardous Properties of Chemical Substances; 2. JohnLiebman, Wiley J.F.; & Greer,Sons, Inc.: A. The Hoboken, Chemistry NJ, of USA, Peroxides 2006;; John pp. 719–740. Wiley & Sons: Hoboken, NJ, USA, 2006; Volume 3. 3.2. Liebman,Klapötke, T.M.;J.F.; Greer, Wloka, A. T. The Peroxide Chemistry explosives. of Peroxides In Patai’s; John Chemistry Wiley & of Sons: Functional Hoboken, Groups NJ,; John USA, Wiley 2006; & Volume Sons, Ltd.: 3. 3. Klapötke,Hoboken, T.M.; NJ, USA, Wloka, 2009. T. Peroxide explosives. In Patai’s Chemistry of Functional Groups; John Wiley & Sons, Ltd.: 4. Hoboken,Denisov, E.T.; NJ, Denisova,USA, 2009. T.G.; Pokidova, T.S. Diacyl peroxides, peroxy esters, polyatomic, and organometallic 4. Denisov,peroxides. E.T.; In Handbook Denisova, of Free T.G.; Radical Pokidova, Initiators; JohnT.S. WileyDiacyl & Sons,peroxides, Inc.: Hoboken, peroxy NJ,esters, USA, polyatomic, 2005; pp. 129–282. and 5. organometallicGaylord, N.G.; peroxides. Mandal, B.M.; In Handbook Martan, of M. Free Peroxide-induced Radical Initiators; polymerization John Wiley & Sons, of norbornene. Inc.: Hoboken,J. Polym. NJ, USA, Sci. Polym.2005; pp. Lett. 129–282. Ed. 1976 , 14, 555–559. [CrossRef] 6.5. Gaylord,Emami, S.H.; N.G.; Salovey, Mandal, R.; B.M.; Hogen-Esch, Martan, T.E. M. Peroxide-mediatedPeroxide-induced crosslinkingpolymerization of poly(ethylene of norbornene. oxide). J. Polym.J. Polym. Sci. Sci.Polym. Part Lett. A Polym. Ed. 1976 Chem., 14, 2002555–559., 40, 3021–3026. [CrossRef] 7.6. Emami,Russell, S.H.; K.E. FreeSalovey, radical R.; graftHogen-Esch, polymerization T.E. Peroxi andde-mediated copolymerization crosslinking at higher of temperatures.poly(ethylene Prog.oxide). Polym. J. Polym. Sci. Sci.2002 Part, 27, A 1007–1038. Polym. Chem. [CrossRef 2002, ]40, 3021–3026. 8.7. Russell,Adam, W.K.E.Peroxide Free radical Chemistry: graft polymerization Mechanistic and and Preparative copolymerization Aspects ofat Oxygenhigher temperatures. Transfer; Wiley-VCH Prog. Polym. Verlag Sci. 2002GmbH, 27 &, 1007–1038. Co. KGaA: Weinheim, Germany, 2005. 9.8. Adam,Mishra, W. M.; Peroxide Yagci, Y.Chemistry:Handbook Mech of Vinylanistic Polymers: and Preparative Radical Polymerization,Aspects of Oxygen Process, Transfer and; TechnologyWiley-VCH, 2nd Verlag ed.; GmbHCRC Press, & Co. Taylor KGaA: & FrancisWeinheim, Group: Germany, Boca Raton, 2005. FL, USA, 2008; p. 784. 10.9. Mishra,Ukuku, D.O.;M.; Yagci, Bari, Y. L.; Handbook Kawamoto, of Vinyl S. Hydrogen Polymers: peroxide. Radical Polymerization, In Decontamination Process, of and Fresh Technology and Minimally, 2nd ed.; Processed CRC ProducePress, Taylor; Wiley-Blackwell: & Francis Group: Hoboken, Boca NJ,Raton, USA, FL, 2012; USA, pp. 2008; 197–214. p. 784. 11.10. Ukuku,Kitis, M. D.O.; Disinfection Bari, L.; of wastewaterKawamoto, withS. Hydrogen peracetic acid:peroxide. A review. In DecontaminationEnviron. Int. 2004 of, 30Fresh, 47–55. and [CrossRefMinimally] Processed Produce; Wiley-Blackwell: Hoboken, NJ, USA, 2012; pp. 197–214. 11. Kitis, M. Disinfection of wastewater with peracetic acid: A review. Environ. Int. 2004, 30, 47–55.

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