2. Academic Validation
  3. Structure-guided design of novel HEPT analogs with enhanced potency and safety: From Isopropyl-HEPTs to Cyclopropyl-HEPTs

Structure-guided design of novel HEPT analogs with enhanced potency and safety: From Isopropyl-HEPTs to Cyclopropyl-HEPTs

  • Eur J Med Chem. 2022 Nov 24;246:114939. doi: 10.1016/j.ejmech.2022.114939.
Ruo-Lan Zhou 1,  Zhiran Ju 1,  Christophe Pannecouque 2,  Erik De Clercq 2,  Shuai Wang 3,  Fen-Er Chen 4
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical Science and Technology, Zhejiang University of Technology, Hangzhou, 310014, China.
  • 2 Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000, Leuven, Belgium.
  • 3 Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai, 200433, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai, 200433, China. Electronic address: shuaiwang@fudan.edu.cn.
  • 4 Institute of Pharmaceutical Science and Technology, Zhejiang University of Technology, Hangzhou, 310014, China; Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai, 200433, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai, 200433, China. Electronic address: rfchen@fudan.edu.cn.
PMID: 36442370 DOI: 10.1016/j.ejmech.2022.114939
Abstract

Members of the HEPT class are potential non-nucleoside inhibitors of HIV-1 Reverse Transcriptase. Our previously disclosed one representative HEPT analog 2 produced potent inhibitory activity against wild-type HIV-1 (EC50 = 63.0 nM), but its high cytotoxicity and low selectivity index still needs to be improved (CC50 = 34.0 μM, SI = 565). In this work, a series of novel cyclopropyl-substituted HEPT analogs were developed by substituting a cyclopropyl ring for the isopropyl group at the C-5 position of 2 with the purpose of improving its potency and safety. Of this series, the most potent compound 9h featuring a 2,5-fluoro substitution on the C-6 benzene ring exerted significantly increased inhibitory activity toward wild-type HIV-1 (EC50 = 0.017 μM), which was 4-fold more active than the lead compound 2. The cytotoxicity of 9h was also reduced with much higher selectivity index (SI > 2328). This compound possessed good pharmacokinetics profiles and potential safety: (1) No obvious in vitro inhibition effect toward CYP Enzyme and hERG was observed in 9h; (2) The single-dose acute toxicity test did not induce mice death and obvious pathological damage; (3) Excellent oral bioavailability of 9h (F= 86%) in rats was unveiled. These results provide valuable guidance for further development of HEPT anti-HIV-1 drugs.

Keywords

Cyclopropyl; HEPT; HIV; NNRTI; Safety.

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