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

Kaijun Jin; Minjie Liu; Chunlin Zhuang; Erik De Clercq; Christophe Pannecouque; Ge Meng; Fener Chen

doi:10.1016/j.apsb.2019.09.007

Acta Pharmaceutica Sinica B (Feb 2020)

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

Kaijun Jin,
Minjie Liu,
Chunlin Zhuang,
Erik De Clercq,
Christophe Pannecouque,
Ge Meng,
Fener Chen

Affiliations

Kaijun Jin: Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433 China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433 China
Minjie Liu: Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433 China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433 China
Chunlin Zhuang: Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433 China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433 China
Erik De Clercq: Rega Institute for Medical Research, KU Leuven, Leuven B-3000 Belgium
Christophe Pannecouque: Rega Institute for Medical Research, KU Leuven, Leuven B-3000 Belgium
Ge Meng: Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433 China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433 China; Corresponding authors. Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai, 200433, China. Tel./fax: +86 21 65643811.
Fener Chen: Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433 China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433 China; Corresponding authors. Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai, 200433, China. Tel./fax: +86 21 65643811.

DOI: https://doi.org/10.1016/j.apsb.2019.09.007
Journal volume & issue: Vol. 10, no. 2
pp. 344 – 357

Abstract

Read online

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 structure–activity relationship and PK profiles were also discussed. KEY WORDS: HIV-1, NNRTIs, NP-DATAs, BP-DATAs, Positional adaptability, Molecular modeling

Published in Acta Pharmaceutica Sinica B

ISSN: 2211-3835 (Print); 2211-3843 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.sciencedirect.com/journal/acta-pharmaceutica-sinica-b

About the journal