title: Pyridobenzothiazole derivatives as new chemotype targeting the HCV NS5B polymerase.
abstract: Hepatitis C virus (HCV) infection has been recognized as the major cause of liver failure that can lead to hepatocellular carcinoma. Among all the HCV proteins, NS5B polymerase represents a leading target for drug discovery strategies. Herein, we describe our initial research efforts towards the identification of new chemotypes as allosteric NS5B inhibitors. In particular, the design, synthesis, in vitro anti-NS5B and in cellulo anti-HCV evaluation of a series of 1-oxo-1H-pyrido[2,1-b][1,3]benzothiazole-4-carboxylate derivatives are reported. Some of the newly synthesized compounds showed an IC(50) ranging from 11 to 23 μM, and molecular modeling and biochemical studies suggested that the thumb domain could be the target site for this new class of NS5B inhibitors.
authors.affiliation: Dipartimento di Chimica e Tecnologia del Farmaco, University of Perugia, 06123 Perugia, Italy. giuseppe.manfroni@unipg.it
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Manfroni
authors.forename: Francesco
authors.initials: F
authors.lastname: Meschini
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Barreca
authors.forename: Pieter
authors.initials: P
authors.lastname: Leyssen
authors.forename: Alberta
authors.initials: A
authors.lastname: Samuele
authors.forename: Nunzio
authors.initials: N
authors.lastname: Iraci
authors.forename: Stefano
authors.initials: S
authors.lastname: Sabatini
authors.forename: Serena
authors.initials: S
authors.lastname: Massari
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maga
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.forename: Violetta
authors.initials: V
authors.lastname: Cecchetti
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D002460:Cell Line; D003198:Computer Simulation; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016174:Hepacivirus / Q000201:enzymology*; D006801:Humans; D017434:Protein Structure, Tertiary; D012984:Software; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C005465:benzothiazole