Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Chemistry, Medicinal, Pharmacology & Pharmacy, HIV-1, DAPY, NNRTIs, NNIBP, Tolerant regions, REVERSE-TRANSCRIPTASE INHIBITORS, DRUG-RESISTANCE, DERIVATIVES, DISCOVERY, MUTATION, ASSAY, Anti-HIV Agents, Cell Line, Tumor, Cell Survival, Dose-Response Relationship, Drug, HIV Reverse Transcriptase, Humans, Microbial Sensitivity Tests, Models, Molecular, Molecular Structure, Pyrimidines, Reverse Transcriptase Inhibitors, Structure-Activity Relationship, Thiophenes, 0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry, 1115 Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry, 3214 Pharmacology and pharmaceutical sciences, 3404 Medicinal and biomolecular chemistry, 3405 Organic chemistry

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-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.