Synthesis, biological evaluation and molecular modeling of 4,6-diarylpyrimidines and diarylbenzenes as novel non-nucleosides HIV-1 reverse transcriptase inhibitors

A series of novel 4,6-diarylpyrimidines (4,6-DAPY) and diarylbenzenes (DABE) compounds were synthesized and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). Among them, the most potent HIV-1 inhibitors were 8b, 8d, 14b and 18 (EC50 = 0.049, 0.381, 0.599 and 0.398 μM, respectively), with HIV-1 inhibitory activity improved or similar to nevirapine (NVP, EC50 = 0.097 μM) and delavirdine (DEV, EC50 = 0.55 μM). The other compounds displayed moderate activity (8c, EC50 = 5.25 μM) or were inactive (8a and 14a) against HIV-1 replication. Molecular modeling studies were performed with the synthesized compounds in complex with the wild-type reverse transcriptase (RT). A correlation was found between the anti-HIV activity and the electrostatic energy of interaction with Lys101 residue. These findings enrich the SAR of these Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) families.

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► Novel NNRTIs scaffolds 4,6-diarylpyrimidines and diarylbenzenes were synthesized.
► Four compounds exhibited excellent potency against wild-type HIV-1 strain IIIB.
► Compounds with a 2,4,6-trimethyl substitution on wing II displayed inactivity.
► Molecular modeling showed that these compounds have lost interaction with Lys101.
► These conclusions are important for the future design of potent NNRTI.