Boronic acid-containing diarylpyrimidine derivatives as novel HIV-1NNRTIs: Design, synthesis and biological evaluation  

作　　者：Da Feng Fenju Wei Yanying Sun Prem Prakash Sharma Tao Zhang Hao Lin Brijesh Rathi 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 for Translational Chemistry and Drug Discovery,Department of Chemistry,Hansraj College,University of Delhi,Delhi 110007,India [3]Rega Institute for Medical Research,Laboratory of Virology and Chemotherapy,K.U.Leuven,Leuven B-3000,Belgium [4]China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province,Ji'nan 250012,China [5]Suzhou Research Institute,Shandong University,Suzhou 215123,China

出　　处：《Chinese Chemical Letters》2021年第12期4053-4057,共5页中国化学快报（英文版）

基　　金：financial support from the National Natural Science Foundation of China (Nos. 81973181, 81903453);Shandong Provincial Natural Science Foundation (No. ZR2019BH011);Natural Science Foundation of Jiangsu Province (No. BK2019041035);China Postdoctoral Science Foundation (Nos. 2019T120596, 2018M640641);Science Foundation for Outstanding Young Scholars of Shandong Province (No. ZR2020JQ31);Science Foundation for Excellent Young Scholars of Shandong Province (No. ZR2020YQ61);National Science and Technology Major Projects for "Major New Drugs Innovation and Development" (2019ZX09301126);Shandong Provincial Key Research and Development Project (Nos. 2017CXGC1401, 2019JZZY021011);Foreign cultural and educational experts Project (No. GXL20200015001);the Taishan Scholar Program at Shandong Province and KU Leuven (No. GOA 10/014)。

摘　　要：Drug resistance remains to be a serious problem with type Ⅰ human immunodeficiency virus(HIV-1) nonnucleoside reverse transcriptase inhibitors(NNRTIs). A series of novel boronic acid-containing diarylpyrimidine(DAPY) derivatives were designed via bioisosterism and scaffold-hopping strategies,taking advantage of the ability of a boronic acid group to form multiple hydrogen bonds. The target compounds were synthesized and evaluated for their anti-HIV activities and cytotoxicity in MT-4 cells.Compound 10 j yielded the most potent activity and turned out to be a single-digit nanomolar inhibitor towards the HIV-1 ⅢB [wild-type(WT) strain], L100 I and K103 N strains, with 50% effective concentration(EC_(50)) values of 7.19–9.85 nmol/L. Moreover, 10 j inhibited the double-mutant strain RES056 with an EC_(50) value of 77.9 nmol/L, which was 3.3-more potent than that of EFV(EC_(50)= 260 nmol/L) and comparable to that of ETR(EC_(50)= 32.2 nmol/L). 10j acted like classical NNRTIs with high affinity for WT HIV-1 reverse transcriptase(RT) with 50% inhibition concentration(IC_(50)) value of 0.1837 μmol/L. Furthermore,molecular dynamics simulation indicated that 10 j was proposed as a promising molecule for fighting against HIV-1 infection through inhibiting RT activity. Overall, the results demonstrated that 10 j could serve as a lead molecule for further modification to address virus-drug resistance.

关 键 词：HIV-1 NNRTIS NNIBP DAPY Boronic acid Molecular dynamics simulation 

分 类 号：TQ460.1[化学工程—制药化工]