Structure-based design and optimization lead to the identification of novel dihydrothiopyrano[3,2-d]pyrimidine derivatives as potent HIV-1 inhibitors against drug-resistant variants  

作　　者：Zhao Wang Heng Zhang Zhen Gao Zihao Sang Erik De Clercq Christophe Pannecouque Dongwei Kang Peng Zhan Xinyong Liu 

机构地区：[1]Department of Medicinal Chemistry,Key Laboratory of Chemical Biology(Ministry of Education),School of Pharmaceutical Sciences,Cheeloo College of Medicine,Shandong University,Jinan 250012,China [2]Rega Institute for Medical Research,Laboratory of Virology and Chemotherapy,K.U.Leuven,Leuven B-3000,Belgium [3]China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province,Jinan 250012,China [4]Suzhou Research Institute,Shandong University,Suzhou 215123,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第3期1257-1282,共26页药学学报（英文版）

基　　金：financial support from the National Natural Science Foundation of China(NSFC nos.81973181 and 81903453);Science Foundation for Outstanding Young Scholars of Shandong Province(ZR2020JQ31,China);Science Foundation for Excellent Young Scholars of Shandong Province(ZR2020YQ61,China);Foreign Cultural and Educational Experts Project(GXL20200015001,China);China Postdoctoral Science Foundation(2022M721948);Shandong Province Natural Science Foundation for Youths(ZR2023QH217,China);Natural Science Foundation of Jiangsu Province(BK20230252,China);Qilu Young Scholars Program of Shandong University;Taishan Scholar Program at Shandong Province。

摘　　要：With our continuous endeavors in seeking potent anti-HIV-1 agents,we reported here the discovery,biological characterization,and druggability evaluation of a class of nonnucleoside reverse transcriptase inhibitors.To fully explore the chemical space of the NNRTI-binding pocket,novel series of dihydrothiopyrano[3,2-d]pyrimidines were developed by employing the structure-based design strategy.Most of the derivatives were endowed with prominent antiviral activities against HIV-1 wild-type and resistant strains at nanomolar levels.Among them,compound 23h featuring the aminopiperidine moiety was identified as the most potent inhibitor,with EC50values ranging from 3.43 to 21.4 nmol/L.Especially,for the challenging double-mutants F227L+V106A and K103N+Y181C,23h exhibited 2.3-to 14.5-fold more potent activity than the first-line drugs efavirenz and etravirine.Besides,the resistance profiles of 23h achieved remarkable improvement compared to efavirenz and etravirine.The binding target of 23h was further confirmed to be HIV-1 reverse transcriptase.Molecular modeling studies were also performed to elucidate the biological evaluation results and give guidance for the optimization campaign.Furthermore,no apparent inhibition of the major CYP450 enzymes and hERG channel was observed for 23h.Most importantly,23h was characterized by good pharmacokinetic properties and excellent safety in vivo.Collectively,23h holds great promise as a potential candidate for its effective antiviral efficacy and favorable drug-like profiles.

关 键 词：HIV-1 Reverse transcriptase Dihydrothiopyrano[3 2-d]pyrimidine Antiviral agent 

分 类 号：R914[医药卫生—药物化学]