Improving the Positional Adaptability: Structure-based Design of Biphenyl-substituted Diaryltriazines As Novel Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors

Overview

Journal Acta Pharm Sin B

Publisher Elsevier

Specialty Pharmacology

Date 2020 Feb 22

PMID 32082978

Citations 7

Authors

Kaijun Jin

Minjie Liu

Chunlin Zhuang

Erik De Clercq

Christophe Pannecouque

Ge Meng

Fener Chen

Affiliations

Soon will be listed here.

Abstract

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 EC 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 and 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 (). 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.

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