Privileged scaffold inspired design of novel oxime-biphenyl-DAPYs in treatment of HIV-1.

Novel oxime-biphenyl-DAPYs were designed and synthesized by a privileged scaffold inspired strategy, exhibiting promising anti-HIV activity, low cytotoxicity and high selectivity index. • Fourteen oxime-biphenyl-DAPYs were designed by a privileged scaffold inspired strategy. • These compounds possessed up to nanomolar potency and low toxicity against wild-type HIV-1-infected cells. • Compound 7d displayed a high potency against WT and E138K mutant strains (EC 50 = 12.1 nM, 0.027 µM). Oxime is a key pharmacophore in drug development. The biphenyl diarylpyrimidines (DAPYs) have been developed by our group as novel non-nucleoside reverse transcriptase inhibitors (NNRTIs). In this study, fourteen oxime-biphenyl-DAPYs were designed and synthesized through a privileged scaffold inspired design strategy. They exhibited promising activity toward wild type HIV-1 and single mutant strains. Compound 7d was found to be the most potent one against both wild type (EC 50 = 12.1 nM) and E138K mutant strains (EC 50 = 0.0270 µM). It also had a much lower cytotoxicity (CC 50 > 292 µM) and higher selective index (SI > 24105) than those of the FDA-approved drugs efavirenz and etravirine. Molecular docking and dynamics simulation predicted and disclosed the binding mode of compound 7d with the RT, providing the explanation on the antiviral activity. These results were helpful for subsequent structural optimizations in anti-HIV-1 drug discovery. [ABSTRACT FROM AUTHOR]