New adamantane-containing compounds targeting rimantadine-resistant influenza virus A/PR/8/34: molecular design, synthesis and SAR study

Four types of adamantane-containing compounds were designed by modifying molecules with proven activity against resistant influenza A viral strains or mutated M2 channel of the virion envelope. Three series were obtained, excluding 5'-methyl-5'H-spiro[adamantane-2,4'-thiazol]-2'-amine, since no intramolecular cyclization of 1-tert-butyl-3-(2- vinyladamantan-2-yl)thiourea occurred in the reaction with HBr or bromine. 2,7-Diazaspiro[3.5]nonane comprising derivatives of adamantane and new series of rimantadine amides have manifested high cytotoxicity, while acceptable selectivity was observed for ester analogues of the latter, and three novel esters demonstrated potent antiviral activity (IC₅₀ = 1.5–12.6 µM vs. 67 µM for rimantadine) against the rimantadine-resistant influenza virus A/PR/8/34.