title: Inhibitory Effect of 2,3,5,6-Tetrafluoro-4-[4-(aryl)-1H-1,2,3-triazol-1-yl]benzenesulfonamide Derivatives on HIV Reverse Transcriptase Associated RNase H Activities.
abstract: The HIV-1 ribonuclease H (RNase H) function of the reverse transcriptase (RT) enzyme catalyzes the selective hydrolysis of the RNA strand of the RNA:DNA heteroduplex replication intermediate, and represents a suitable target for drug development. A particularly attractive approach is constituted by the interference with the RNase H metal-dependent catalytic activity, which resides in the active site located at the C-terminus p66 subunit of RT. Herein, we report results of an in-house screening campaign that allowed us to identify 4-[4-(aryl)-1H-1,2,3-triazol-1-yl]benzenesulfonamides, prepared by the "click chemistry" approach, as novel potential HIV-1 RNase H inhibitors. Three compounds (9d, 10c, and 10d) demonstrated a selective inhibitory activity against the HIV-1 RNase H enzyme at micromolar concentrations. Drug-likeness, predicted by the calculation of a panel of physicochemical and ADME properties, putative binding modes for the active compounds, assessed by computational molecular docking, as well as a mechanistic hypothesis for this novel chemotype are reported.
authors.affiliation: Dipartimento di Chimica e Farmacia, Università di Sassari, Via Vienna 2, I-07100 Sassari, Italy. nikpal@uniss.it.
authors.forename: Nicolino
authors.initials: N
authors.lastname: Pala
authors.affiliation: Dipartimento di Scienze della Vita e dell'Ambiente-Sezione Biomedica, Università di Cagliari, Cittadella Universitaria SS554, I-09042 Monserrato, Italy. francescaesposito@unica.it.
authors.forename: Francesca
authors.initials: F
authors.lastname: Esposito
authors.affiliation: Dipartimento di Chimica, Università di Parma, Parco Area delle Scienze 17/A, I-43124 Parma, Italy. dominga.rogolino@unipr.it.
authors.forename: Dominga
authors.initials: D
authors.lastname: Rogolino
authors.affiliation: Dipartimento di Chimica, Università di Parma, Parco Area delle Scienze 17/A, I-43124 Parma, Italy. mauro.carcelli@unipr.it.
authors.forename: Mauro
authors.initials: M
authors.lastname: Carcelli
authors.affiliation: Dipartimento di Chimica e Farmacia, Università di Sassari, Via Vienna 2, I-07100 Sassari, Italy. vsanna@uniss.it.
authors.forename: Vanna
authors.initials: V
authors.lastname: Sanna
authors.affiliation: Dipartimento di Chimica e Farmacia, Università di Sassari, Via Vienna 2, I-07100 Sassari, Italy. mpalomba@uniss.it.
authors.forename: Michele
authors.initials: M
authors.lastname: Palomba
authors.affiliation: Rega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium. lieve.naesens@kuleuven.be.
authors.forename: Lieve
authors.initials: L
authors.lastname: Naesens
authors.affiliation: Dipartimento di Scienze della Vita e dell'Ambiente-Sezione Biomedica, Università di Cagliari, Cittadella Universitaria SS554, I-09042 Monserrato, Italy. angela.corona@unica.it.
authors.forename: Angela
authors.initials: A
authors.lastname: Corona
authors.affiliation: Dipartimento di Scienze della Vita e dell'Ambiente-Sezione Biomedica, Università di Cagliari, Cittadella Universitaria SS554, I-09042 Monserrato, Italy. nicole.grandi2@gmail.com.
authors.forename: Nicole
authors.initials: N
authors.lastname: Grandi
authors.affiliation: Dipartimento di Scienze della Vita e dell'Ambiente-Sezione Biomedica, Università di Cagliari, Cittadella Universitaria SS554, I-09042 Monserrato, Italy. tramon@unica.it.|Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), I-09042 Monserrato, Italy. tramon@unica.it.
authors.forename: Enzo
authors.initials: E
authors.lastname: Tramontano
authors.affiliation: Dipartimento di Chimica e Farmacia, Università di Sassari, Via Vienna 2, I-07100 Sassari, Italy. mario.sechi@uniss.it.
authors.forename: Mario
authors.initials: M
authors.lastname: Sechi
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D062105:Molecular Docking Simulation; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology*; D000096926:Benzenesulfonamides
chemical_list: D019380:Anti-HIV Agents; D054303:HIV Reverse Transcriptase; D018894:Reverse Transcriptase Inhibitors; D013449:Sulfonamides; D000096926:Benzenesulfonamides
keywords: 4-[4-(aryl)-1H-1,2,3-triazol-1-yl]benzenesulfonamides; HIV-1 RNase H; click-chemistry; docking