Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 21, Issue 11, Pages 3262-3271Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2013.03.041
Keywords
L-Phenylalanine; D-Phenylalanine; Rhodanine; Knoevenagel condensation; Ullmann condensation; HCV NS5B polymerase
Funding
- Department of Pharmaceutical Sciences of St. John's University
- St. John's University [579-1110]
- National Institute of Health [DK066837, CA153147]
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Hepatitis C virus (HCV) NS5B polymerase is a key target for anti-HCV therapeutics development. Herein, we report the synthesis and in vitro evaluation of anti-NS5B polymerase activity of a molecular hybrid of our previously reported lead compounds 1 (IC50 = 7.7 mu M) and 2 (IC50 = 10.6 mu M) as represented by hybrid compound 27 (IC50 = 6.7 mu M). We have explored the optimal substituents on the terminal phenyl ring of the 3-phenoxybenzylidene moiety in 27, by generating a set of six analogs. This resulted in the identification of compound 34 with an IC50 of 2.6 mu M. To probe the role of stereochemistry towards the observed biological activity, we synthesized and evaluated the D-isomers 41 (IC50 = 19.3 mu M) and 45 (IC50 = 5.4 mu M) as enantiomers of the L-isomers 27 and 34, respectively. The binding site of compounds 32 and 34 was mapped to palm pocket-I (PP-I) of NS5B. The docking models of 34 and 45 within the PP-I of NS5B were investigated to envisage the molecular mechanism of inhibition. (C) 2013 Elsevier Ltd. All rights reserved.
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