Design,synthesis,and biological evaluation of benzo[4,5]thieno[2,3-d]pyrimidine derivatives as novel HIV-1 NNRTIs  

作　　者：Bairu Meng Zongji Zhuo Han Yu Sining Tao Zixuan Chen 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,Ji’nan 250012,China [2]Laboratory of Virology and Chemotherapy,Rega Institute for Medical Research,K.U.Leuven,Leuven B-3000,Belgium [3]China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province,Ji’nan 250012,China

出　　处：《Chinese Chemical Letters》2024年第6期344-348,共5页中国化学快报（英文版）

基　　金：financial support from the National Natural Science Foundation of China(NSFC,Nos.81973181,82273773);Shandong Provincial Natural Science Foundation(Nos.ZR2020YQ61,ZR2020JQ31);Qilu Young Scholars Program of Shandong University and Taishan Scholar Program at Shandong Province。

摘　　要：Inspired by our previous studies to discover novel human immunodeficiency virus-1(HIV-1)nonnucleoside reverse transcriptase inhibitors(NNRTIs)by targeting the tolerant region II of the NNRTIs binding pocket(NNIBP),a series of novel benzo[4,5]thieno[2,3-d]pyrimidine derivatives were designed through structure-based drug design as novel potent HIV-1 NNRTIs.The results showed that compound16b was the most active inhibitor,exhibiting 50% effective concentration(EC50)values from 0.021μmol/L to 0.298μmol/L against wild-type(WT)and a panel of NNRTIs-resistant HIV-1 strains.Moreover,16b was demonstrated with a significantly low 50% cytotoxicity concentration(CC_(50))value(>200μmol/L)and high selectivity index(SI)values.In addition,16b yielded moderate reverse transcriptase(RT)enzyme inhibition with a 50% inhibition concentration(IC_(50))value of 0.183μmol/L,which demonstrated that it acted as HIV-1 NNRTIs.The binding mode of 16b with RT was also illustrated via molecular docking.Overall,this work provided a novel lead compound for developing potent HIV-1 NNRTIs.

关 键 词：HIV-1 NNRTIS DAPYs Tolerant regionⅡ Drug design 

分 类 号：O626[理学—有机化学]