2. Academic Validation
  3. Discovery of 2-pyridone derivatives as potent HIV-1 NNRTIs using molecular hybridization based on crystallographic overlays

Discovery of 2-pyridone derivatives as potent HIV-1 NNRTIs using molecular hybridization based on crystallographic overlays

  • Bioorg Med Chem. 2014 Mar 15;22(6):1863-72. doi: 10.1016/j.bmc.2014.01.054.
Wenmin Chen 1,  Peng Zhan 1,  Diwakar Rai 1,  Erik De Clercq 2,  Christophe Pannecouque 2,  Jan Balzarini 2,  Zhongxia Zhou 1,  Huiqing Liu 3,  Xinyong Liu 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, No. 44, West Culture Road, 250012 Jinan, Shandong, PR China.
  • 2 Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
  • 3 Institute of Pharmacology, School of Medicine, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China.
  • 4 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, No. 44, West Culture Road, 250012 Jinan, Shandong, PR China. Electronic address: xinyongl@sdu.edu.cn.
PMID: 24581546 DOI: 10.1016/j.bmc.2014.01.054
Abstract

Based on crystallographic overlays of the known inhibitors TMC125 and R221239 complexed in RT, we designed a novel series of 4-phenoxy-6-(phenylamino)pyridin-2(1H)-one derivatives as HIV NNRTIs by molecular hybridization approach. The biological testing results indicated that 2-pyridone scaffold of these inhibitors was indispensable for their anti-HIV-1 activity, and substitution of halogen at the 3-position of the 2-pyridone ring would decrease the anti-HIV activity. Four most potent compounds had anti-HIV-1 IIIB activities at low micromolar concentrations (EC₅₀=0.15-0.84 μM), comparable to that of nevirapine and delavidine. Some compounds were selected to test their anti-HIV-1 RT inhibitory action and to perform molecular modeling studies to predict the binding mode of these 2-pyridone derivatives.

Keywords

2-Pyridone; Docking; Drug design; HIV; Molecular hybridization; NNRTIs.

Figures