title: Carbonic anhydrase inhibitors: synthesis and inhibition of the human carbonic anhydrase isoforms I, II, IX and XII with benzene sulfonamides incorporating 4- and 3-nitrophthalimide moieties.
abstract: A series of 4 and 5 nitro-1,3-dioxoisoindolin-2-yl benzenesulfonamide derivatives (compounds 1-8) was synthesized by reaction of benzenesulfonamide derivatives with 4 and 3-nitrophthalic anhydrides. These new sulfonamides were investigated as inhibitors of the zinc metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) and more specifically against the human (h) cytosolic isoforms hCA I and II and the transmembrane, tumor-associated hCA IX and XII. Most of the novel compounds were medium potency-weak hCA I inhibitors (Kis in the range of 295-10,000 nM), but were more effective hCA II inhibitors (Kis of 1.7-887 nM). The tumor-associated hCA IX was also inhibited, with Kis in the micromolar range, whereas against hCA XII the inhibition constants were in the range of 90-3,746 nM. The structure-activity relationship (SAR) with this series of sulfonamides is straightforward, with the main features leading to good activity for each isoforms being established. The high sequence hCA alignment homology and molecular docking studies was performed in order to rationalize the activities reported and binding mode to different hCA as inhibitors.
authors: Department of Pharmaceutical Sciences, Birla Institute of Technology, Mesra, Ranchi 835215, India. Electronic address: kalyansethi@gmail.com.
authors: Kalyan K
authors: KK
authors: Sethi
authors: Department of Pharmaceutical Sciences, Birla Institute of Technology, Mesra, Ranchi 835215, India.
authors: Saurabh M
authors: SM
authors: Verma
authors: Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Firenze), Italy; Università degli Studi di Firenze, NEUROFARBA Department, Section of Pharmaceutical Chemistry, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy.
authors: Muhammet
authors: M
authors: Tanç
authors: Università degli Studi di Firenze, NEUROFARBA Department, Section of Pharmaceutical Chemistry, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy.
authors: Gaultier
authors: G
authors: Purper
authors: Università degli Studi di Firenze, NEUROFARBA Department, Section of Pharmaceutical Chemistry, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy.
authors: Gaetan
authors: G
authors: Calafato
authors: Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Firenze), Italy.
authors: Fabrizio
authors: F
authors: Carta
authors: Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Firenze), Italy; Università degli Studi di Firenze, NEUROFARBA Department, Section of Pharmaceutical Chemistry, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy. Electronic address: claudiu.supuran@unifi.it.
authors: Claudiu T
authors: CT
authors: Supuran
mesh_terms: D024401:Carbonic Anhydrase I / Q000737:chemistry* / Q000378:metabolism; D024402:Carbonic Anhydrase II / Q000737:chemistry* / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry*; D006801:Humans; D054833:Isoindoles / Q000737:chemistry*; D007546:Isoquinolines / Q000737:chemistry*; D062105:Molecular Docking Simulation; D020033:Protein Isoforms / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides; D000096926:Benzenesulfonamides
chemical_list: D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; D002257:Carbonic Anhydrase Inhibitors; D054833:Isoindoles; D007546:Isoquinolines; D020033:Protein Isoforms; D013449:Sulfonamides; D000096926:Benzenesulfonamides; C046066:3-nitrophthalimide
keywords: Benzenesulfonamide; Docking; Human carbonic anhydrase inhibitors; Nitro-1,3-dioxoisoindolin-2-yl benzenesulfonamide; Sequence alignment; Structure activity relationship