Synthesis of new N‐(3‐oxo‐1‐thia‐4‐azaspiro[4.5]decan‐4‐yl)pyridine‐3‐carboxamide derivatives and evaluation of their anti‐influenza virus and antitubercular activities

Abstract

We here report the synthesis, structural characterization, and evaluation of the antiviral and antitubercular activities of a novel series of hybrid spirothiazolidinone derivatives (2a–f and 3a–f) containing the nicotinohydrazide moiety, which is an isomer form of the approved antitubercular drug isoniazid. When evaluated for activity against influenza A/H1N1, A/H3N2, and B viruses, three of the new compounds proved to possess specific antiviral activity against the influenza A/H3N2 virus. The most active analog 3a, bearing a 2,8‐dimethyl group at the spiro ring, displayed an antiviral EC50 value of 5.2 µM. Compound 3a produced no cytotoxicity at 100 µM, the highest concentration tested, giving a selectivity index of at least 19. Structure–activity relationship analysis indicated that the absence of the methyl substituent at the 2‐position and the presence of a bulky substituent at the 8‐position of the spirothiazolidinone system caused a significant decrease in antiviral activity. The in vitro antitubercular activity of compounds 2a–f and 3a–f was determined for six different drug‐sensitive/drug‐resistant laboratory strains and clinical isolates of Mycobacterium tuberculosis. Compounds 2c, 2d, 3b, 3c, and 3d showed weak antitubercular activity against different strains, with MIC values of 125–250 μM.

Influenza A virus hemagglutinin: from classical fusion inhibitors to proteolysis targeting chimera-based strategies in antiviral drug discovery

“…The results showed that the imidazo[2,1-b][1,3]thiazole moiety could be replaced by 2-hydroxyphenyl (Figure 9B), 1-adamantyl (Figure 9C), or 5-chloro-2-hydroxyphenyl (Figure 9D), as the antiviral efficacy and selectivity were not drastically diminished [76][77][78]. Recent studies also showed the feasibility of incorporating an indole moiety, leading to a compound (Figure 9E) that showed an EC 50 of 1 nmol/L in H3N2 virus-infected MDCK cells [79]. Docking calculations performed using the THBQ-and arbidol-bound complexes with HA showed that this latter compound adopts similar binding poses, with the azaspiro group being inserted into the hydrophobic pocket and the indole group oriented towards the pocket mouth.…”