Identification of novel potent HIV-1 inhibitors by exploiting the tolerant regions of the NNRTIs binding pocket

With our previously identified potent NNRTIs 25a and HBS-11c as leads, series of novel thiophene[3,2-d]pyrimidine thiophene[2,3-d]pyrimidine derivatives were designed via molecular hybridization strategy. All the target compounds evaluated for their anti-HIV-1 activity cytotoxicity in MT-4 cells. Compounds 16a1 16b1 turned out to be most inhibitors against WT mutant HIV-1 strains (L100I, K103N, E138K), with EC50 values ranging from 0.007 ?M 0.043 ?M. Gratifyingly, exhibited significantly reduced (CC50 > 217.5 ?M) improved water solubility (S = 49.3 ?g/mL at pH 7.0) compared lead < 1 7.0, CC50 2.30 ?M). Moreover, docking was also conducted rationalize structure-activity relationships these understand key interactions binding pocket.