Expansion of the S–CN-DABO scaffold to exploit the impact on inhibitory activities against the non-nucleoside HIV-1 reverse transcriptase

The α-cyanoarylmethyl-3, 4-dihydropyrimidin-4(3H)-ones (S-CN-DABOs) were reported as a kind of reverse transcriptase inhibitors of human immunodeficiency virus type-1 (HIV-1) by our group in 2007. In this paper, we proposed to expand the S-CN-DABO scaffold to enrich the structure-activity relationship (SAR) of the phenyl ring that was predicted to be located in the W229 hydrophobic pocket. Thirty-nine S-CN-DABO derivatives were manufactured to explore the impact on inhibitory activities against the non-nucleoside HIV-1 reverse transcriptase. These analogues displayed up to low nanomolar activity against wild-type (WT) HIV-1 and good activity against several clinically relevant resistant mutant viruses, especially rilpivirine-associated resistant mutant E138K strain. The inhibitory ability toward the RT enzyme was significantly improved. Compound B23 with a 2, 6-difluoro-phenyl group showed inhibitory effects with an EC50 value of 20.8 nM against HIV-1 WT strain, and an EC50 of 50 nM targeting mutant E138K, which were about 20-fold better than the lead compound B1. Molecular docking analysis elucidated the biological activity and offered a structural insight for follow-up research. In addition, compound B23 also showed favorable drug-like properties in vitro and in vivo. There was no significant inhibition of hERG (IC50 > 40 μM), no apparent CYP enzymatic inhibitory activity and acute toxicity in mouse models. Perfect oral bioavailability of compound B23 was revealed (F = 164%, SD rats). In summary, these S-CN-DABOs compounds could be further optimized and modified for promising drug candidates in anti-HIV clinical therapy.