Novel modifications in the series of O-(2-phthalimidoethyl)-N-substituted thiocarbamates and their ring-opened congeners as non-nucleoside HIV-1 reverse transcriptase inhibitors

Abstract The structure–activity relationships (SARs) of N -aryl- O -(2-phthalimidoethyl)thiocarbamates (C-TCs) and their imide ring-opened congeners (O-TCs) as non-nucleoside HIV-1 reverse transcriptase inhibitors were further investigated. The SAR strategy involved modifications of the N -phenyl ring followed by the hybridization of the most promising N -aryl and O -(2-phthalimidoethyl) substructures. The role of stereochemistry and tert -butyl substitution of the phthalimidoethyl moiety on activity was also investigated. Seventy-six analogues were prepared by parallel solution-phase synthesis. Twenty-two C-TCs displayed nanomolar activity against wild-type HIV-1 and a number of analogues were effective against the Y181C mutant. Compound 56 combined the highest activity so far identified against Y181C (EC 50  = 1.3 μM) with good potency against the K103R mutant (EC 50  = 4.8 μM). Docking simulations helped to rationalize the SARs.