Studies on new thiazolidinone and spirothiazolidinone derivatives

Antiviral drugs, particularly those against the influenza virus, are thought to be therapeutically insufficient. The discovery of novel anti influenza drugs is required due to inadequacy against a possible influenza pandemic. Some compounds bearing thiazolidinone ring exhibit antiviral activity, thus they are potential drug candidates. In this study, compounds including 1-thia-4-azaspiro[4.5]decan-3-on (11a-c, 12a-c, 13a-c, 14a-e, 15a, 15b, 16a-c) or 2-substituted-1,3-thiazolidin-4-one (17-21) structure were synthesized. Alicyclic ketones or aromatic aldehydes were reacted with benzohydrazide, 2-methoxybenzohydrazide or phenylacetohydrazide to afford hydrazones (4a-g, 5a-e, 6a-e, 7-10), which were later reacted with mercaptoacetic acid or 2-mercaptopropanoic acid to give targeted cyclization products. Mechanisms of the reactions were discussed. The structures were confirmed by elemental analysis, UV, IR, 1H NMR, 13C NMR (DEPT, HSQC and HMBC). Compounds were evaluated against a large virus panel including influenza A/H1N1, influenza A/H3N2 and influenza B viruses. 16a, 15a and 14a-c were found to be active against influenza A/H3N2 virus as comparable level with zanamivir, ribavirin, amantadine and rimantadine (16a, 0,0031 mM; 15a, 0,0022 mM; 14a, 0,0273 mM; 14b, 0,0015 mM; 14c, 0,00042 mM). 16a showed less activity to reovirus-1 compared with mycophenolic acid (16a, 0,048 mM, mycophenolic acid, 0,0028 mM). 14e and 16b displayed biological activity to punta toro virus (14e, 0,007 mM; 16b, 0,0095 mM; mycophenolic acid, 0,0089 mM). Also lower activity was displayed by 5e to respiratory syncytial virus compared with ribavirin (5e, 0,061 mM, ribavirin, 0,015 mM). The antiviral activity profiles of these thiazolidinone derivatives will shed light on the design of novel antiviral drugs.