Bioorganic and Medicinal Chemistry p. 1863 - 1872 (2014)
Update date:2022-07-30
Topics: Molecular Hybridization HIV-1 NNRTIs Crystallographic Overlays 2-Pyridone Derivatives
Chen, Wenmin
Zhan, Peng
Rai, Diwakar
De Clercq, Erik
Pannecouque, Christophe
Balzarini, Jan
Zhou, Zhongxia
Liu, Huiqing
Liu, Xinyong
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.
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