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Updated: Aug 15, 2025
Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
Development of novel S-N3-DABO derivatives as potent non-nucleoside reverse transcriptase inhibitors with improved
Xu Ling1, Qing-Qing Hao1, Wen-Juan Huang2
1Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai, 200433, PR China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai, 200433, PR China; Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, PR China.
Abstract:
Following on our initial discovery of S-CN-DABOs as non-nucleoside reverse transcriptase inhibitors (NNRTIs), a series of novel S-N3-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 (EC50 = 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 (EC50 = 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 (IC50 = 0.080 μM) than B1 (IC50 = 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).
