Development of novel S-N 3 -DABO derivatives as potent non-nucleoside reverse transcriptase inhibitors with improved potency and selectivity.

Following on our initial discovery of S-CN-DABOs as non-nucleoside reverse transcriptase inhibitors (NNRTIs), a series of novel S-N ₃ -DABO derivatives F1-F31 were developed by substituting the cyano group of S-CN-DABOs with azide group. Some of these compounds were conferred significantly increased potency against wild-type HIV-1 and clinically observed mutant strains. Remarkably, the best compound F10 exerted a 7-fold improvement in potency (EC ₅₀  = 0.053 μM) and 12.5-fold higher selectivity (SI = 6818) in MT-4 cells infected with wild-type HIV-1, compared to that of the parent compound B1 (EC ₅₀  = 370 nM, SI = 547). The anti-HIV-1 activity of F10 against the tested mutant strains was prominently enhanced. For wild-type reverse transcriptase, it was approximately 19-fold more potent (IC ₅₀  = 0.080 μM) than B1 (IC ₅₀  = 1.51 μM). It was not found that this analog had significant inhibition of hERG, CYP, and acute toxicity after a single dose of F10 (1.0 g/kg).
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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