title: Studies on Cycloheptathiophene-3-carboxamide Derivatives as Allosteric HIV-1 Ribonuclease H Inhibitors.
abstract: Despite the significant progress achieved with combination antiretroviral therapy in the fight against human immunodeficiency virus (HIV) infection, the difficulty to eradicate the virus together with the rapid emergence of multidrug-resistant strains clearly underline a pressing need for innovative agents, possibly endowed with novel mechanisms of action. In this context, owing to its essential role in HIV genome replication, the reverse transcriptase associated ribonuclease H (RNase H) has proven to be an appealing target. To identify new RNase H inhibitors, an in-house cycloheptathiophene-3-carboxamide library was screened; this led to compounds endowed with inhibitory activity, the structural optimization of which led to the catechol derivative 2-(3,4-dihydroxybenzamido)-N-(pyridin-2-yl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide (compound 33) with an IC50 value on the RNase H activity in the nanomolar range. Mechanistic studies suggested selective inhibition of the RNase H through binding to an innovative allosteric site, which could be further exploited to enrich this class of inhibitors.
authors.affiliation: Dipartimento di Scienze della Vita e dell'Ambiente, Cittadella Universitaria di Monserrato, SS554, 09042, Monserrato, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Corona
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Perugia, Via del Liceo 1, 06123, Perugia, Italy.
authors.forename: Jenny
authors.initials: J
authors.lastname: Desantis
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Perugia, Via del Liceo 1, 06123, Perugia, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Massari
authors.affiliation: Dipartimento di Scienze della Vita e dell'Ambiente, Cittadella Universitaria di Monserrato, SS554, 09042, Monserrato, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Distinto
authors.affiliation: Basic Research Laboratory, National Cancer Institute, Frederick, MD, 21702-1201, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Masaoka
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Perugia, Via del Liceo 1, 06123, Perugia, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Sabatini
authors.affiliation: Dipartimento di Scienze della Vita e dell'Ambiente, Cittadella Universitaria di Monserrato, SS554, 09042, Monserrato, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Esposito
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Perugia, Via del Liceo 1, 06123, Perugia, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Manfroni
authors.affiliation: Dipartimento di Scienze della Vita e dell'Ambiente, Cittadella Universitaria di Monserrato, SS554, 09042, Monserrato, Italy.
authors.forename: Elias
authors.initials: E
authors.lastname: Maccioni
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Perugia, Via del Liceo 1, 06123, Perugia, Italy.
authors.forename: Violetta
authors.initials: V
authors.lastname: Cecchetti
authors.affiliation: Laboratory of Virology and Chemotherapy, Department of Microbiology and Immunology, Rega Institute for Medical Research-KU Leuven, Minderbroedersstraat 10, 3000, Leuven, Belgium.
authors.forename: Christophe
authors.initials: C
authors.lastname: Pannecouque
authors.affiliation: Basic Research Laboratory, National Cancer Institute, Frederick, MD, 21702-1201, USA.
authors.forename: Stuart F J
authors.initials: SF
authors.lastname: Le Grice
authors.affiliation: Dipartimento di Scienze della Vita e dell'Ambiente, Cittadella Universitaria di Monserrato, SS554, 09042, Monserrato, Italy. tramon@unica.it.
authors.forename: Enzo
authors.initials: E
authors.lastname: Tramontano
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Perugia, Via del Liceo 1, 06123, Perugia, Italy. oriana.tabarrini@unipg.it.
authors.forename: Oriana
authors.initials: O
authors.lastname: Tabarrini
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D008958:Models, Molecular; D015394:Molecular Structure; D016914:Ribonuclease H / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000619893:2-(3,4-dihydroxybenzamido)-N-(pyridin-2-yl)-5,6,7,8-tetrahydro-4H-cyclohepta(b)thiophene-3-carboxamide; D019380:Anti-HIV Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D013876:Thiophenes; D016914:Ribonuclease H
keywords: allosterism antiviral agents inhibitors medicinal chemistry ribonucleases