Original articles
Kaijun Jin, Minjie Liu, Chunlin Zhuang, Erik De Clercq, Christophe Pannecouque, Ge Meng, Fener Chen. Improving the positional adaptability: structurebased design of biphenyl-substituted diaryltriazines as novel non-nucleoside HIV-1 reverse transcriptase inhibitors[J]. Acta Pharmaceutica Sinica B, 2020, 10(2): 344-357

Improving the positional adaptability: structurebased design of biphenyl-substituted diaryltriazines as novel non-nucleoside HIV-1 reverse transcriptase inhibitors
Kaijun Jina,b, Minjie Liua,b, Chunlin Zhuanga,b, Erik De Clercqc, Christophe Pannecouquec, Ge Menga,b, Fener Chena,b
a Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China;
b Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China;
c Rega Institute for Medical Research, KU Leuven, Leuven B-3000, Belgium
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 5j and 6k 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 structureeactivity relationship and PK profiles were also discussed.
Key words:    HIV-1    NNRTIs    NP-DATAs    BP-DATAs    Positional adaptability    Molecular modeling   
Received: 2019-02-08     Revised: 2019-07-08
DOI: 10.1016/j.apsb.2019.09.007
Funds: This research work was financially supported by National Natural Science Foundation of China under Grant Nos. 21871055 and 21372050 as well as Shanghai Municipal Natural Science Foundation under Grant No. 13ZR1402200 (China). We would like to thank the technical assistance of Mr. Kris Uyttersprot, Mrs. Kristien Erven, and Mrs. Cindy Heens from the RegaInstititute of Leuven University for the HIVexperiments and HIV RT polymerase assays.
Corresponding author: Ge Meng, Fener Chen     Email:mgfudan@fudan.edu.cn;rfchen@fudan.edu.cn
Author description:
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Kaijun Jin
Minjie Liu
Chunlin Zhuang
Erik De Clercq
Christophe Pannecouque
Ge Meng
Fener Chen

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