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

Abstract

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