title: Discovery of in vitro antitubercular agents through in silico ligand-based approaches.
abstract: The development of new anti-tubercular agents represents a constant challenge mostly due to the insurgency of resistance to the currently available drugs. In this study, a set of 60 molecules were selected by screening the Asinex and the ZINC collections and an in house library by means of in silico ligand-based approaches. Biological assays in Mycobacterium tuberculosis H37Ra ATCC 25177 strain highlighted (±)-1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethyl-4-(3,4-dichlorophenyl)piperazine-1-carboxylate (5i) and 3-(4-chlorophenyl)-5-(2,4-dimethylpyrimidin-5-yl)-2-methylpyrazolo[1.5-a]pyrimidin-7(4H)-one (42) as the most potent compounds, having a Minimum Inhibitory Concentration (MIC) of 4 and 2 μg/mL respectively. These molecules represent a good starting point for further optimization of effective anti-TB agents.
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, 00185 Roma, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: De Vita
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, 00185 Roma, Italy.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Pandolfi
authors.affiliation: Dipartimento del Farmaco, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Roma, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Cirilli
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, 00185 Roma, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Scipione
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, 00185 Roma, Italy; Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, 00185 Roma, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Di Santo
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, 00185 Roma, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Friggeri
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53019 Siena, Italy; Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Roma, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Mori
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53019 Siena, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Fiorucci
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53019 Siena, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Maccari
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53019 Siena, Italy.
authors.forename: Robert Selwyne
authors.initials: RS
authors.lastname: Arul Christopher
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53019 Siena, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Zamperini
authors.affiliation: Dipartimento di Scienze della Vita e dell'Ambiente, Università degli Studi di Cagliari, Via Porcell 4, 09124 Cagliari, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Pau
authors.affiliation: Dipartimento di Scienze della Vita e dell'Ambiente, Università degli Studi di Cagliari, Via Porcell 4, 09124 Cagliari, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: De Logu
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, 00185 Roma, Italy. Electronic address: silvano.tortorella@uniroma1.it.
authors.forename: Silvano
authors.initials: S
authors.lastname: Tortorella
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53019 Siena, Italy; Sbarro Institute for Cancer Research & Molecular Medicine, Center for Biotechnology, College of Science & Technology, Temple University, BioLife Science Building, Suite 333, 1900 N 12th Street, Philadelphia, PA 19122, USA. Electronic address: maurizio.botta@unisi.it.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology; D003198:Computer Simulation; D055808:Drug Discovery; D008024:Ligands; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D054852:Small Molecule Libraries
chemical_list: D000995:Antitubercular Agents; D008024:Ligands; D054852:Small Molecule Libraries
keywords: Anti-tubercular agents; Azoles; Phenyl-pyrazolopyrimidinones; Virtual screening