Improving the positional adaptability:structurebased design of biphenyl-substituted diaryltriazines as novel non-nucleoside HIV-1 reverse transcriptase inhibitors  

作　　者：Kaijun Jin Minjie Liu Chunlin Zhuang Erik De Clercq Christophe Pannecouque Ge Meng Fener Chen 

机构地区：[1]Engineering Center of Catalysis and Synthesis for Chiral Molecules,Department of Chemistry,Fudan University,Shanghai 200433,China [2]Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs,Shanghai 200433,China [3]Rega Institute for Medical Research,KU Leuven,Leuven B-3000,Belgium

出　　处：《Acta Pharmaceutica Sinica B》2020年第2期344-357,共14页药学学报（英文版）

基　　金：financially supported by National Natural Science Foundation of China under Grant Nos.21871055 and21372050;Shanghai Municipal Natural Science Foundation under Grant No.13ZR1402200(China).

摘　　要：In order to improve the positional adaptability of our previously reported naphthyl diaryltriazines(NP-DATAs),synthesis of a series of novel biphenyl-substituted diaryltriazines(BP-DATAs)with a flexible side chain attached at the C-6 position is presented.These compounds exhibited excellent potency against wild-type(WT)HIV-1 with EC50 values ranging from 2.6 to 39 nmol/L and most of them showed low nanomolar anti-viral potency against a panel of HIV-1 mutant strains.Compounds 5 j and 6 k had the best activity against WT,single and double HIV-1 mutants and reverse transcriptase(RT)enzyme comparable to two reference drugs(EFV and ETR)and our lead compound NP-DATA(1).Molecular modeling disclosed that the side chain at the C-6 position of DATAs occupied the entrance channel of the HIV-1 reverse transcriptase non-nucleoside binding pocket(NNIBP)attributing to the improved activity.The preliminary structure-activity relationship and PK profiles were also discussed.

关 键 词：HIV-1 NNRTIS NP-DATAs BP-DATAs Positional ADAPTABILITY Molecular modeling 

分 类 号：R914[医药卫生—药物化学] TQ463.5[医药卫生—药学]