Mendeleev Commun., 2016, 26, 214–216 – 214 – Mendeleev Communications © 2016 Mendeleev Communications. Published by ELSEVIER B.V. on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the Russian Academy of Sciences. Ribavirin (Virazole, 1- -D-ribofuranosyl-1,2,4-triazole-3-carbox- amide) is a nucleoside antiviral agent with a wide antiviral spectrum used against both RNA and DNA viruses. 1,2 Several hypotheses are existing concerning targets and activity mecha- nism of ribavirin, 3–5 which is more of a mystery. The ribavirin analogues bearing bulky substituents at the 5-position of the triazole ring were first mentioned quite recently. 6 Later, some syntheses of similar analogues 1–3 as well as antiviral and anti- cancer activities were reported. 7–12 Generally authors modified the molecule of ribavirin itself or its nucleoside precursors using Pd-catalyzed cross-coupling reactions. Thus, the anomeric con- figuration of the product was predetermined since the modification occurred at the 5-position of the triazole ring. Unfortunately, this approach is limited by the substrate diversity and the substituent type containing multiple bonds. The classical method includes the heterocyclic base synthesis with subsequent ribosylation, chemical or chemoenzymatic, and allows one to expand the variety of substituents. However, only a small number of the ribavirin analogues were obtained by this route, possibly because of low synthetic availability of respective substituted heterocyclic bases. Previously reported by our group synthetic pathways of various 5-substituted 1-H-1,2,4-triazole-3-carboxylic acids 13 provided a set of heterocyclic bases for the ribavirin analogue synthesis (Scheme 1). 5-Substituted ethyl 1-H-1,2,4-triazole-3-carboxylates 4a–h were obtained from -N-acylamidrazones and corresponding acid chlorides with subsequent amide preparation by treatment with ammonia. Nucleoside 6a was synthesized from amide 5a by the described procedure 14,15 (Scheme 2). The activity of this ribavirin analogue against reproduction of viruses that cause hazardous human infections including human/avian influenza A virus was investigated. 14 Amides 5b–h appeared to be unsuitable substrates for recombinant purine nucleoside phosphorylase (EC 2.4.2.1) from E. Coli, and this was in agreement with our previous conclusions. 16 Since this limitation made impossible the use of stereoselective chemoenzymatic synthesis as for 5a, the protected nucleosides 7b–h were obtained by condensation of ethyl esters 4b–h with ribose tetraacetate at 160 °C in the presence of acid catalyst by the modified method 17 (Scheme 3). Originally, this method includes melting of D-ribofuranose tetra- acetate with subsequent addition of triazole and catalyst, at reduced pressure. The yield of the nucleoside with protecting groups (for instance 7b) was only 28% by this route. We succeeded in improving the yield to 54% by dissolving all reaction com- Novel 5-alkyl(aryl)-substituted ribavirine analogues: synthesis and antiviral evaluation Mikhail V. Chudinov,* a Andrey V. Matveev, a Alexander N. Prutkov, a Irina D. Konstantinova, b Ilja V. Fateev, b Vladimir S. Prasolov, c Olga A. Smirnova, c Alexander V. Ivanov, c Georgy A. Galegov d and Petr G. Deryabin d a M. V. Lomonosov Institute of Fine Chemical Technologies, Moscow Technological University, 117571 Moscow, Russian Federation. E-mail: mikle@irims.ru b M. M. Shemyakin–Yu. A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russian Federation c V. A. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russian Federation d D. I. Ivanovsky Research Institute of Virology, 123098 Moscow, Russian Federation DOI: 10.1016/j.mencom.2016.04.012 COOEt NH HN HN R O N N H N COOEt R 30–90% 20–80% O HO HO OH N N N R H 2 N O 8 examples Novel 5-alkyl(aryl)-substituted 1- -D-ribofuranosyl-1,2,4-tri- azole-3-carboxamides were prepared in three steps. Their antiviral activity was evaluated. O HO HO OH N N N H 2 N O 1 O HO HO OH N N N H 2 N O 2 F O HO HO OH N N N H 2 N O 3 C C CF 3 HN N N COOEt R 4a–h NH 4 OH EtOH, reflux, 72 h HN N N CONH 2 R 5a–h 80–95% a R = Me b R = Et c R = Pr d R = Pr i e R = cyclopropyl f R = Bu i g R = Bu t h R = Ph Scheme 1