title: Lead Development of Thiazolylsulfonamides with Carbonic Anhydrase Inhibitory Action.
abstract: A series of congeners structurally related to pritelivir, N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide, a helicase-primase inhibitor for the treatment of herpes simplex virus infections, was prepared. The synthesized primary and secondary sulfonamides were investigated as inhibitors of six physiologically and pharmacologically relevant human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, the cytosolic enzymes hCA I and II, the mitochondrial ones hCA VA and VB, and the transmembrane, tumor associated hCA IX and XII. Low nanomolar inhibition KIvalues were detected for all of them, with a very interesting and well-defined structure-activity relationship. As many CAs are involved in serious pathologies, among which are cancer, obesity, epilepsy, glaucoma, etc., sulfonamide inhibitors as those reported here may be of interest as drug candidates. Furthermore, pritelivir itself is an effective inhibitor of some CAs, also inhibiting whole blood enzymes from several mammalian species, which may be a favorable pharmacokinetic feature of the drug which can be transported throughout the body bound to blood CA I and II.
authors.affiliation: Sezione di Scienze Farmaceutiche e Nutraceutiche, NEUROFARBA, Università degli Studi di Firenze , Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: Fabrizio
authors.identifier: 0000-0002-1141-6146
authors.initials: F
authors.lastname: Carta
authors.affiliation: AiCuris Anti-Infective Cures GmbH , Friedrich-Ebert-Strasse 475, 42117 Wuppertal, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Birkmann
authors.affiliation: AiCuris Anti-Infective Cures GmbH , Friedrich-Ebert-Strasse 475, 42117 Wuppertal, Germany.
authors.forename: Tamara
authors.initials: T
authors.lastname: Pfaff
authors.affiliation: AiCuris Anti-Infective Cures GmbH , Friedrich-Ebert-Strasse 475, 42117 Wuppertal, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Buschmann
authors.affiliation: AiCuris Anti-Infective Cures GmbH , Friedrich-Ebert-Strasse 475, 42117 Wuppertal, Germany.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Schwab
authors.affiliation: AiCuris Anti-Infective Cures GmbH , Friedrich-Ebert-Strasse 475, 42117 Wuppertal, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Zimmermann
authors.affiliation: Sezione di Scienze Farmaceutiche e Nutraceutiche, NEUROFARBA, Università degli Studi di Firenze , Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Maresca
authors.affiliation: Sezione di Scienze Farmaceutiche e Nutraceutiche, NEUROFARBA, Università degli Studi di Firenze , Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: Claudiu T
authors.identifier: 0000-0003-4262-0323
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology*; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D020033:Protein Isoforms; D013449:Sulfonamides; D013844:Thiazoles; D002256:Carbonic Anhydrases