Synthesis, structure–activity relationships, and docking studies of N-phenylarylformamide derivatives (PAFAs) as non-nucleoside HIV reverse transcriptase inhibitors

A series of N-phenylarylformamide derivatives (PAFAs) with anti-wild-type HIV-1 activity (EC50 values) ranging from 0.3 nM to 5.1 nM and therapeutic index (TI) ranging from 10 616 to 271 000 were identified as novel non-nucleoside reverse transcriptase inhibitors. Among them, compound 13g (EC50 = 0.30 nM, TI = 184 578), 13l (EC50 = 0.37 nM, TI = 212 819), 13m (EC50 = 0.32 nM, TI = 260 617) and 13r (EC50 = 0.27 nM, TI = 271 000) displayed the highest activity against this type virus nearly as potent as lead compound GW678248. Moreover, all of them were also active to inhibit the double mutant strain A17 (K103N + Y181C) with EC50 values of 0.29 μM, 0.14 μM, 0.10 μM and 0.27 μM, respectively. In particular, compound 13m, which showed broad-spectrum anti-HIV activity, was also effective to inhibit the HIV-2 ROD replication within 4.37 μM concentration.

Led by novel benzophenone derivative GW678248, a series of N-phenylarylformamide derivatives (PAFAs) were identified as potent non-nucleoside HIV reverse transcriptase inhibitors.Figure optionsDownload as PowerPoint slideHighlights
► N-Phenylarylformamide derivatives (PAFAs) as novel NNRTIs.
► The anti-wild-type HIV-1 activity (EC50 values) ranging from 0.3 nM to 5.1 nM.
►  The preliminary SARs and the docking modes were investigated.