2. Academic Validation
  3. Design and synthesis of a new series of modified CH-diarylpyrimidines as drug-resistant HIV non-nucleoside reverse transcriptase inhibitors

Design and synthesis of a new series of modified CH-diarylpyrimidines as drug-resistant HIV non-nucleoside reverse transcriptase inhibitors

  • Eur J Med Chem. 2014 Jul 23:82:600-11. doi: 10.1016/j.ejmech.2014.05.059.
Ge Meng 1,  Yang Liu 2,  Aqun Zheng 3,  Fener Chen 4,  Wenxue Chen 5,  Erik De Clercq 6,  Christophe Pannecouque 6,  Jan Balzarini 6
Affiliations

Affiliations

  • 1 School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China. Electronic address: mengge@mail.xjtu.edu.cn.
  • 2 School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
  • 3 School of Science, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, PR China.
  • 4 Department of Chemistry, Fudan University, Shanghai 200433, PR China. Electronic address: rfchen@fudan.edu.cn.
  • 5 Department of Chemistry, Fudan University, Shanghai 200433, PR China.
  • 6 Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium.
PMID: 24952305 DOI: 10.1016/j.ejmech.2014.05.059
Abstract

This article reports the design, synthesis and Antiviral evaluation of a new series of non-nucleoside Reverse Transcriptase inhibitors (NNRTIs). The basic skeleton of these target 18 molecules is diarylpyrimidine featuring a substituted amino group between the pyrimidine scaffold and the aryl wing. All of the new compounds have been characterized by spectra analysis. The entire target molecules were evaluated for their in vitro anti-HIV activity with controlling group of FDA approved drugs. Most of them showed good to potent activities against wild-type (WT) HIV-1 with IC50 values in the range of 0.0175-69.21 μM. 2-(4-Cyanophenylamino)-4-(2-cyanovinylphenylhydrazonomethyl)pyrimidine (1d) displayed potent anti-HIV-1 activity against WT HIV-1 with a selectivity index (SI) of 106367 and an IC50 value of 1.75 nM, which was 47 fold lower than that of AZT. Compound 1d also showed a broad-spectrum inhibitory activity, with an IC50 value of 5.33 μM and 5.05 μM against both HIV-1 double-mutated (K103N/Y181C) strain and HIV-2 strain, respectively. The preliminary structure-activity relationship (SAR) was also investigated. The binding modes with HIV-1 RT for both the wild type and mutant type have also been discussed.

Keywords

Cyanide group; Diarylpyrimidines; Docking analysis; Double mutant HIV-1; Non-nucleoside HIV RT inhibitors; SAR.

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