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

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.

Publication year:2020

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CSS-citation score:1

Authors:International

Authors from:Higher Education

Accessibility:Open