Identification of Novel Diarylpyrimidines as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors by Exploring the Primer Grip Region

Tao Zhang, Zhongxia Zhou, Fabao Zhao, Zihao Sang, Erik De Clercq, Christophe Pannecouque, Dongwei Kang, Peng Zhan, Xinyong Liu

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

HIV-1 reverse transcriptase (RT) plays a crucial role in the viral replication cycle, and RT inhibitors can represent a promising pathway in treating AIDS. To explore the primer grip region of HIV-1 RT, using -CH2O- as a linker, substituted benzene or pyridine rings were introduced into the left wing of diarylpyrimidines (DAPYs). A total of 17 compounds with new structures were synthesized. It showed that all compounds exhibited anti-HIV-1 (wild-type) activity values ranging from 7.6–199.0 nM. Among them, TF2 (EC50 = 7.6 nM) showed the most potent activity, which was better than that of NVP (EC50 = 122.6 nM). Notably, compared with RPV (CC50 = 3.98 μM), TF2 (CC50 > 279,329.6 nM) showed low cytotoxicity. For HIV-1 mutant strains K103N and E138K, most compounds showed effective activities. Especially for K103N, TF2 (EC50 = 28.1 nM), TF12 (EC50 = 34.7 nM) and TF13 (EC50 = 28.0 nM) exhibited outstanding activity, being superior to that of NVP (EC50 = 7495.1 nM) and EFV (EC50 = 95.1 nM). Additionally, TF2 also showed the most potent activity against E138K (EC50 = 44.0 nM) and Y181C mutant strains (EC50 = 139.3 nM). In addition, all the compounds showed strong enzyme inhibition (IC50 = 0.036–0.483 μM), which demonstrated that their target was HIV-1 RT. Moreover, molecular dynamics simulation studies were implemented to predict the binding mode of TF2 in the binding pocket of wild-type and K103N HIV-1 RT.

Original languageEnglish
Article number1438
JournalPharmaceuticals
Volume15
Issue number11
DOIs
StatePublished - Nov 2022
Externally publishedYes

Keywords

  • HIV-1
  • NNRTIs
  • diarylpyrimidines
  • reverse transcriptase

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