Pharmacophore-fusing design of pyrimidine sulfonylacetanilides as potent non-nucleoside inhibitors of HIV-1 reverse transcriptase

[Display omitted] •Twenty-seven sulfonylacetanilide-DAPYs were designed by a pharmacophore fusing strategy.•These compounds possessed up to single-digit nanomolar potency and low toxicity against wild-type (WT) HIV-1-infected cells.•Compound 51 displayed marked inhibitory activity against WT, and mutant L100I, K103N, Y181C, Y188L, and E138K HIV-1 mutants. Twenty-seven derivatives (40–66) were generated by pharmacophore fusing of sulfonylacetanilide-diarylpyrimidine (1) with rilpivirine or biphenyl-diarylpyrimidines. They displayed up to single-digit nanomolar activity against wild-type (WT) virus and various drug-resistant mutant strains in HIV-1-infected MT-4 cells, thereby targeting the reverse transcriptase (RT) enzyme. Compound 51 displayed exceptionally potent activity against WT virus (EC50 = 6 nM) and several mutant strains (L100I, EC50 = 8 nM, K103N, EC50 = 6 nM, Y181C, EC50 = 26 nM, Y188L, EC50 = 122 nM, E138K, EC50 = 26 nM). The structure-activity relationships of the newly obtained pyrimidine sulfonylacetanilides were also elucidated. Molecular docking analysis explained the activity and provided a structural insight for follow-up research.