title: Structure-based discovery of pyrazolobenzothiazine derivatives as inhibitors of hepatitis C virus replication.
abstract: The NS5B RNA-dependent RNA polymerase is an attractive target for the development of novel and selective inhibitors of hepatitis C virus replication. To identify novel structural hits as anti-HCV agents, we performed structure-based virtual screening of our in-house library followed by rational drug design, organic synthesis, and biological testing. These studies led to the identification of pyrazolobenzothiazine scaffold as a suitable template for obtaining novel anti-HCV agents targeting the NS5B polymerase. The best compound of this series was the meta-fluoro-N-1-phenyl pyrazolobenzothiazine derivative 4a, which exhibited an EC50 = 3.6 μM, EC90 = 25.6 μM, and CC50 > 180 μM in the Huh 9-13 replicon system, thus providing a good starting point for further hit evolution.
authors: Dipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica Farmaceutica II, Università degli Studi di Perugia, Via del Liceo 1, 06123 Perugia, Italy. lbarreca@unipg.it
authors: Maria Letizia
authors: ML
authors: Barreca
authors: Giuseppe
authors: G
authors: Manfroni
authors: Pieter
authors: P
authors: Leyssen
authors: Johan
authors: J
authors: Winquist
authors: Neerja
authors: N
authors: Kaushik-Basu
authors: Jan
authors: J
authors: Paeshuyse
authors: Ramalingam
authors: R
authors: Krishnan
authors: Nunzio
authors: N
authors: Iraci
authors: Stefano
authors: S
authors: Sabatini
authors: Oriana
authors: O
authors: Tabarrini
authors: Amartya
authors: A
authors: Basu
authors: U Helena
authors: UH
authors: Danielson
authors: Johan
authors: J
authors: Neyts
authors: Violetta
authors: V
authors: Cecchetti
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology*; D008958:Models, Molecular; D011487:Protein Conformation; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D011720:Pyrazoles; D017361:Viral Nonstructural Proteins; C031280:pyrazole; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase