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Citation: Qingqing Hao, Xu Ling, Christophe Pannecouque, Erik De Clercq, Fener Chen. Linker optimization of HEPT derivatives as potent non-nucleoside HIV-1 reverse transcriptase inhibitors: From S=O to CHOR[J]. Chinese Chemical Letters, ;2023, 34(4): 107663. doi: 10.1016/j.cclet.2022.07.006 shu

Linker optimization of HEPT derivatives as potent non-nucleoside HIV-1 reverse transcriptase inhibitors: From S=O to CHOR

a.
Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
b.
Department of Chemistry, Engineering Center of Catalysis and Synthesis for Chiral Molecules, Fudan University, Shanghai 200433, China
c.
Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China
d.
Rega Institute for Medical Research, KU Leuven, Herestraat 49, Leuven B-3000, Belgium

^*

rfchen@fudan.edu.cn

Received Date: 25 May 2022
Revised Date: 30 June 2022
Accepted Date: 5 July 2022
Available Online: 8 July 2022

Figures(5)

A novel series of CHOR-HEPT non-nucleoside HIV-1 reverse transcriptase inhibitors were developed by means of structure-based design strategy based on compound 6 reported previously by our group. Most of these compounds showed moderate to good activity toward wild-type HIV-1 strain with EC₅₀ values in the range of 0.18–51.88 µmol/L and SI values in the range of 4–907. The compound 14aj with a CHOH linker and compound 13i with a CHOTMS linker in this series exhibited improved anti-HIV-1 activity (EC₅₀ = 0.18 µmol/L, and 0.20 µmol/L) with higher selectivity (SI = 907, and 665) as comparison with the lead compound 6 (EC₅₀ = 0.59 µmol/L, SI = 9). These two compounds 14aj and 13i were more sensitive than 6 toward clinically relevant mutant L100I, K103N and E138K viruses, which were further evaluated for their activity against wild-type reverse transcriptase and displayed a good correlation with the cell-based activity. Preliminary molecular modeling investigations provided insight for further structural optimization of HEPT.
- HIV,
- NNRTIs,
- HEPTs,
- RT,
- Optimization
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