[Frontiers in Bioscience 13, 3857-3868, May 1, 2008]
4-Thiazolidinones: a novel class of hepatitis C virus NS5B polymerase inhibitors
1Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103, 2Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, NY 11439, 3Marmara University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Haydarpasa, 34668 Istanbul, Turkey
TABLE OF CONTENTS
In a quest to identify novel compounds targeting HCV viral replicase, we evaluated a new series of 4-thiazolidinone derivatives (18 compounds). Our in vitro NS5B RdRp inhibition analysis with a series of 2¢ ,4¢ -difluoro-4-hydroxybiphenyl-3-carboxylic acid (2-(5-nitro-2-furyl / substituted phenyl)-4-thiazolidinone-3-yl) amides (1-7) yielded IC50 values ranging between 45-75 microM. Of these, lead compound 6: 2¢ ,4¢ -difluoro-4-hydroxybiphenyl-3-carboxylic acid(2-(2-fluorophenyl)-4-thiazolidinone-3-yl)amide exhibited an IC50 value of 48 microM and inhibited NS5B non-competitively with respect to UTP and exhibited a mixed mode of inhibition with respect to RNA. Molecular docking of thiazolidinone derivatives within the allosteric site of NS5B yielded significant correlation between their calculated binding affinity and IC50 values. Taken together, these data suggest that the 4-thiazolidinone scaffold may be optimized for generating new analogues with improved anti-NS5B potency.