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The Evolution of Pleconaril: Modified O-Alkyl Linker Analogs Have

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The Evolution of Pleconaril: Modified O-Alkyl Linker Analogs Have molecules Communication The Evolution of Pleconaril: Modified O-Alkyl Linker Analogs Have Biological Activity towards Coxsackievirus B3 Nancy 1, 2, 1 3 Alexandrina Volobueva y, Anna Egorova y, Anastasia Galochkina , Sean Ekins , Vladimir Zarubaev 1 and Vadim Makarov 2,* 1 Saint-Petersburg Pasteur Institute, Mira str., 14, 197101 Saint Petersburg, Russia; [email protected] (A.V.); [email protected] (A.G.); [email protected] (V.Z.) 2 Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, Leninsky prospect, 33, build. 2, 119071 Moscow, Russia; [email protected] 3 Collaborations Pharmaceuticals, Inc., 840 Main Campus Drive, Lab 3510, Raleigh, NC 27606, USA; [email protected] * Correspondence: [email protected] These authors contributed equally to this work. y Received: 10 February 2020; Accepted: 13 March 2020; Published: 16 March 2020 Abstract: Coxsackieviruses type B are one of the most common causes of mild upper respiratory and gastrointestinal illnesses. At the time of writing, there are no approved drugs for effective antiviral treatment for Coxsackieviruses type B. We used the core-structure of pleconaril, a well-known antienteroviral drug candidate, for the synthesis of novel compounds with O-propyl linker modifications. Some original compounds with 4 different linker patterns, such as sulfur atom, ester, amide, and piperazine, were synthesized according to five synthetic schemes. The cytotoxicity and bioactivity of 14 target compounds towards Coxsackievirus B3 Nancy were examined. Based on the results, the values of 50% cytotoxic dose (CC50), 50% virus-inhibiting dose (IC50), and selectivity index (SI) were calculated for each compound. Several of the novel synthesized derivatives exhibited a strong anti-CVB3 activity (SI > 20 to > 200). These results open up new possibilities for synthesis of further new selective anticoxsackievirus compounds. Keywords: coxsackievirus; coxsackievirus B3 Nancy; viral myocarditis; antivirals; pleconaril 1. Introduction Enteroviruses belonging to the Picornaviridae family are a diverse group of small (30–32 nm size) icosahedral non-enveloped viruses with single-stranded non-segmented positive RNA genome with a poly(A) tail. They are able to survive in harsh environments and can cause both self-limiting infections as well as polio, hand-foot-mouth disease, and heart and central nervous system diseases [1]. Currently, the genus Enterovirus encompasses 15 species: Enterovirus A–L and Rhinovirus A–C. Coxsackieviruses type B (CVBs) are members of Enterovirus B species and include six serotypes (CVB1-6). CVBs are lytic viruses but persistent infection responsible for chronic inflammation within target organs can be established. CVB3 often leads to mild upper respiratory and gastrointestinal illnesses, but it can also cause myocarditis [2,3]. Viral myocarditis is usually associated with dyspnea, arrhythmia, and chest pain and can lead to acute heart failure and sudden death. Currently available treatment is supportive and focuses on the symptomatic factors of disease [4,5]. To date, there are no approved antiviral agents for effective therapy of CVB3 infections. Currently the most advanced approaches for anti-CVB drug design are focused on the search for new direct antivirals, the modification of existing antiviral compounds, and drug repurposing screening [6]. Molecules 2020, 25, 1345; doi:10.3390/molecules25061345 www.mdpi.com/journal/molecules Molecules 2020, 25, 1345 2 of 18 Molecules 2020, 25, x FOR PEER REVIEW 2 of 18 Pleconaril,[6]. Pleconaril, a well-known a well-known antienteroviral antienteroviral drug drug candidate candidate with with the the capsid-binding capsid-binding mechanismmechanism of action, does not cover all of the Coxsackievirus B serotypes, including the typical representative, Coxsackievirus B3 Nancy, whichwhich isis exploredexplored inin thisthis articlearticle [[7–9].7–9]. Previously, wewe have have reported reported that that pleconaril pleconaril resistance resistance was overcome was overcome by unsubstituted by unsubstituted analogues oranalogues by monosubstitution or by monosubstitution in the central in phenyl the central ring [phen10]. Inyl ourring most [10]. recentIn our work,most recent we showed work, the we impact showed of the substitutionimpact of the pattern substitution in the isoxazolepattern in and the phenylisoxazole rings and of phenyl the pleconaril rings of core the pleconaril structure and core their structure effect onand antiviral their effect activity on antiviral [11]. The activity most active [11]. compound The most toactive date compound contains the to 3- dateN,N -dimethylcarbamoylcontains the 3-N,N- groupdimethylcarbamoyl in the isoxazole group ring in and the the isoxazole 3-methyl ring group and inthe the 3-methyl phenyl group ring (Figure in the1 phenyl). ring (Figure 1). It is interesting to investigate how the replacement of the alkyl linker with different different substituents aaffectsffects thethe antienteroviralantienteroviral activity,activity, because because in in the the original original pleconaril pleconaril research research project, project, G.D. G.D. Diana Diana et al.et variedal. varied the the length length of of the the aliphatic aliphatic chain chain only only [12 [12,13].,13]. Thus, Thus, in in the the present present article, article, wewe havehave continuedcontinued our investigation to to study study the the influence influence of of the the plec pleconarilonaril core core structure structure and and various various modifications modifications on onthe theobserved observed antiviral antiviral activity. activity. We We synthesized synthesized compounds compounds with with the the general general structure structure shown in Figure1 ,1, which which have have the theN, NN-dimethylcarbamoyl,N-dimethylcarbamoyl or ethoxycarbonyl or ethoxycarbon oryl methyl or methyl (like pleconaril) (like pleconaril) groups ingroups the isoxazole in the isoxazole ring and the ring 3-methyl and the group 3-methyl in phenyl group ring, in and phenyl then examinedring, and their then inhibition examined activity their againstinhibition Coxsackievirus activity against B3 Coxsackievirus Nancy. B3 Nancy. Figure 1. The Evolution of Pleconaril. 2. Results and Discussion 2. Results and Discussion To explore the impact of the O-alkyl linker modification we, firstly, exchanged an oxygen atom To explore the impact of the O-alkyl linker modification we, firstly, exchanged an oxygen atom for a sulfur atom with conservation of the 3-carbon chain; secondly, we introduced an ester or amide for a sulfur atom with conservation of the 3-carbon chain; secondly, we introduced an ester or amide group into the linker; finally, we completely replaced the alkyl linker with piperazine. Syntheses of the group into the linker; finally, we completely replaced the alkyl linker with piperazine. Syntheses of compounds are presented in Schemes1–4. the compounds are presented in Schemes 1–4. In the Scheme1, the initial benzonitrile 1 was reacted with 5-chloro-1-pentyne in the presence of In the Scheme 1, the initial benzonitrile 1 was reacted with 5-chloro-1-pentyne in the presence of potassium carbonate and potassium iodide in NMP to produce pentynylthiobenzonitrile 2. The reaction potassium carbonate and potassium iodide in NMP to produce pentynylthiobenzonitrile 2. The of 2 with excess of hydroxylamine hydrochloride and potassium carbonate in absolute refluxing reaction of 2 with excess of hydroxylamine hydrochloride and potassium carbonate in absolute ethanol provided amidoxime 3 with a yield of 92%. Cyclization into 1,2,4-oxadiazole 4 was refluxing ethanol provided amidoxime 3 with a yield of 92%. Cyclization into 1,2,4-oxadiazole 4 was carried out using treatment of 3 with trifluoroacetic anhydride in pyridine. The cycloaddition carried out using treatment of 3 with trifluoroacetic anhydride in pyridine. The cycloaddition of the of the S-pentyn-1 linker in 4 and 2-chloro-2-(hydroxyimino)acetic acid ethyl ester 5 or commercial S-pentyn-1 linker in 4 and 2-chloro-2-(hydroxyimino)acetic acid ethyl ester 5 or commercial acetaldoxime resulted in the target compounds 6a,b with yields of 40% and 32%, respectively. Finally, acetaldoxime resulted in the target compounds 6a,b with yields of 40% and 32%, respectively. Finally, (carbethoxy-isoxazolyl)propyl)thio)phenyl)oxadiazole 6a reacted with dimethylamine solution in order (carbethoxy-isoxazolyl)propyl)thio)phenyl)oxadiazole 6a reacted with dimethylamine solution in to synthesize 7 with a yield of 57%. order to synthesize 7 with a yield of 57%. Molecules 2020, 25, 1345 3 of 18 Molecules 2020, 25, x FOR PEER REVIEW 3 of 18 Molecules 2020, 25, x FOR PEER REVIEW 3 of 18 SchemeScheme 1. 1. SynthesisSynthesis ofof 3-(3-methyl-4-((3-(3-substitutedisoxazol-5-yl)propyl)thio)phenyl)-5-3-(3-methyl-4-((3-(3-substitutedisoxazol-5-yl)propyl)thio)phenyl)-5- (trifluoromethyl)-1,2,4-oxadiazoles(trifluoromethyl)-1,2,4-oxadiazoles6a,b 6a,b andand 77.. Reagents and and conditions conditions:: (a) (a)5-chloro-1-pentyne, 5-chloro-1-pentyne, SchemeK2CO3, KI, 1.NMP, Synthesis 65 °C; (b) ofNH 2OH·HCl,3-(3-methyl-4-((3-(3-substit K2CO3, EtOHabs, reflux;utedisoxazol-5-yl)propyl)thio)phenyl)-5- (c) (CF3CO)2O, pyridine, 80–90 °C; K2CO3, KI, NMP, 65 ◦C; (b) NH2OH HCl, K2CO3, EtOHabs, reflux; (c) (CF3CO)2O, pyridine, 80–90 ◦C; (trifluoromethyl)-1,2,4-oxadiazoles(d) 2-chloro-2-(hydroxyimino)acetic· 6a,b acid andethyl 7 .ester Reagents 5, Et 3N,and DMF, conditions 80–90 :°C; (a) (e)5-chloro-1-pentyne, acetaldoxime, N- (d) 2-chloro-2-(hydroxyimino)acetic acid ethyl ester 5, Et3N, DMF, 80–90 ◦C; (e) acetaldoxime, Kchlorosuccinimide,2CO3, KI, NMP, 65 pyridine °C; (b) NHcat, Et2OH·HCl,3N, DMF, K 80–902CO3, °C;EtOH (f)abs dimethylamin, reflux; (c) (CFe solution3CO)2O, 17pyridine, wt.% in 80–90 dioxane, °C; N-chlorosuccinimide, pyridinecat, Et3N, DMF, 80–90 ◦C; (f) dimethylamine solution 17 wt.% in (d)70–80 2-chloro-2-(hydroxyimino)acetic °C. acid ethyl ester 5, Et3N, DMF, 80–90 °C; (e) acetaldoxime, N- dioxane, 70–80 C. chlorosuccinimide,◦ pyridinecat, Et3N, DMF, 80–90 °C; (f) dimethylamine solution 17 wt.% in dioxane, 70–802-Methyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3- °C.
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