2. Academic Validation
  3. Development of novel S-N3-DABO derivatives as potent non-nucleoside reverse transcriptase inhibitors with improved potency and selectivity

Development of novel S-N3-DABO derivatives as potent non-nucleoside reverse transcriptase inhibitors with improved potency and selectivity

  • Eur J Med Chem. 2023 Feb 5;247:115042. doi: 10.1016/j.ejmech.2022.115042.
Xu Ling 1,  Qing-Qing Hao 1,  Wen-Juan Huang 2,  Christophe Pannecouque 3,  Erik De Clercq 3,  Shuai Wang 4,  Fen-Er Chen 5
Affiliations

Affiliations

  • 1 Engineering 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.
  • 2 Engineering 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.
  • 3 Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000, Leuven, Belgium.
  • 4 Engineering 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. Electronic address: shuaiwang@fudan.edu.cn.
  • 5 Engineering 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. Electronic address: rfchen@fudan.edu.cn.
PMID: 36577220 DOI: 10.1016/j.ejmech.2022.115042
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).

Keywords

Azide substitution; HIV-1; NNRTIs; S-CN-DABOs; S-N(3)-DABOs.

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