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

作　　者：Qingqing Hao Xu Ling Christophe Pannecouque Erik De Clercq Fener Chen 

机构地区：[1]Sichuan Research Center for Drug Precision Industrial Technology,West China School of Pharmacy,Sichuan University,Chengdu 610041,China [2]Department of Chemistry,Engineering Center of Catalysis and Synthesis for Chiral Molecules,Fudan University,Shanghai 200433,China [3]Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs,Shanghai 200433,China [4]Rega Institute for Medical Research,KU Leuven,Herestraat 49,Leuven B-3000,Belgium

出　　处：《Chinese Chemical Letters》2023年第4期188-192,共5页中国化学快报（英文版）

基　　金：financially supported by National Natural Science Foundation of China (No. 22077018);National Key R&D Program of China (No. 2017YFA0506000)。

摘　　要：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 EC50values 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.

关 键 词：HIV NNRTIS HEPTs RT OPTIMIZATION 

分 类 号：R914[医药卫生—药物化学]