title: Design and synthesis of L- and D-phenylalanine derived rhodanines with novel C5-arylidenes as inhibitors of HCV NS5B polymerase.
abstract: 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 μM) and 2 (IC50=10.6 μM) as represented by hybrid compound 27 (IC50=6.7 μM). 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 μM. To probe the role of stereochemistry towards the observed biological activity, we synthesized and evaluated the D-isomers 41 (IC50=19.3 μM) and 45 (IC50=5.4 μM) 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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA.
authors.forename: Bhargav A
authors.initials: BA
authors.lastname: Patel
authors.forename: Ramalingam
authors.initials: R
authors.lastname: Krishnan
authors.forename: Nikhil
authors.initials: N
authors.lastname: Khadtare
authors.forename: K R
authors.initials: KR
authors.lastname: Gurukumar
authors.forename: Amartya
authors.initials: A
authors.lastname: Basu
authors.forename: Payal
authors.initials: P
authors.lastname: Arora
authors.forename: Aaditya
authors.initials: A
authors.lastname: Bhatt
authors.forename: Maulik R
authors.initials: MR
authors.lastname: Patel
authors.forename: Dibyendu
authors.initials: D
authors.lastname: Dana
authors.forename: Sanjai
authors.initials: S
authors.lastname: Kumar
authors.forename: Neerja
authors.initials: N
authors.lastname: Kaushik-Basu
authors.forename: Tanaji T
authors.initials: TT
authors.lastname: Talele
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D015195:Drug Design; D016174:Hepacivirus / Q000737:chemistry* / Q000201:enzymology; D062105:Molecular Docking Simulation; D010649:Phenylalanine / Q000737:chemistry*; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D053778:Thiazolidines / Q000138:chemical synthesis* / Q000737:chemistry; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D000998:Antiviral Agents; D053778:Thiazolidines; D017361:Viral Nonstructural Proteins; D010649:Phenylalanine; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase