title: Inhibition of carbonic anhydrase isoforms I, II, IV, VII and XII with carboxylates and sulfonamides incorporating phthalimide/phthalic anhydride scaffolds.
abstract: We report a panel of carboxylates and sulfonamides incorporating phthalic anhydride and phthalimide moieties in their structure and their interaction with the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). They were synthesized from substituted anthranilic acids and trimellitic anhydride chloride, followed by reaction with primary amines and were tested for the inhibition of five physiologically relevant CA isoforms, the human (h) hCA I, II, IV, VII and XII, some of which are involved in serious pathologies (CA II, IV and XII in glaucoma; CA VII in epilepsy; CA XII in some solid tumors). The carboxylic acids were generally poor inhibitors of isoforms hCA I, II and IV but were highly effective, low nanomolar inhibitors of hCA VII and XII. The sulfonamides inhibited all isoforms significantly, and some of them were sub-nanomolar hCA VII inhibitors, although their isoform selectivity was lower compared to the carboxylates. This study proves that carboxylic acids incorporating a phthalic anhydride/phthalimide based scaffold may lead to isoform-selective inhibitors by applying the tail approach, mostly used up until now for obtaining sulfonamide, sulfamide and sulfamate CA inhibitors.
authors.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; Department of Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt. Electronic address: adelazaba@yahoo.com.
authors.forename: Adel S
authors.initials: AS
authors.lastname: El-Azab
authors.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura, Egypt.
authors.forename: Alaa A-M
authors.initials: AA
authors.lastname: Abdel-Aziz
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
authors.forename: Rezk R
authors.initials: RR
authors.lastname: Ayyad
authors.affiliation: Università degli Studi di Firenze, Polo Scientifico, Neurofarba Department and Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Ceruso
authors.affiliation: Università degli Studi di Firenze, Polo Scientifico, Neurofarba Department and Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy. Electronic address: claudiu.supuran@unifi.it.
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000086:Acetazolamide / Q000737:chemistry; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D010796:Phthalic Anhydrides / Q000138:chemical synthesis / Q000737:chemistry*; D010797:Phthalimides / Q000138:chemical synthesis / Q000737:chemistry*; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry*; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D007527:Isoenzymes; D010796:Phthalic Anhydrides; D010797:Phthalimides; D013449:Sulfonamides; D062367:ortho-Aminobenzoates; D000086:Acetazolamide
keywords: Carbonic anhydrase; Carboxylic acid; Isoform-selectivity; Sulfonamide