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 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-4 cells. 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 0.007 μM to 0.043 μM. Gratifyingly, 16b1 exhibited significantly reduced cytotoxicity (CC50 > 217.5 μM) and improved water solubility (S = 49.3 μg/mL at pH 7.0) compared to the lead 25a (S < 1 μg/mL at pH 7.0, CC50 = 2.30 μM). 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.
['Sun|Yanying|Y|', 'Kang|Dongwei|D|', 'Da|Feng|F|', 'Zhang|Tao|T|', 'Li|Pei|P|', 'Zhang|Baodan|B|', 'De Clercq|Erik|E|', 'Pannecouque|Christophe|C|', 'Zhan|Peng|P|', 'Liu|Xinyong|X|']
D019380:Anti-HIV Agents D045744:Cell Line, Tumor D002470:Cell Survival D004305:Dose-Response Relationship, Drug D054303:HIV Reverse Transcriptase D015497:HIV-1 D006801:Humans D008826:Microbial Sensitivity Tests D008958:Models, Molecular D015394:Molecular Structure D011743:Pyrimidines D018894:Reverse Transcriptase Inhibitors D013329:Structure-Activity Relationship D013876:Thiophenes
HIV-1 Tolerant regions NNRTIs DAPY NNIBP