Development of 3-(4-aminosulphonyl)-phenyl-2-mercapto-3H-quinazolin-4-ones as inhibitors of carbonic anhydrase isoforms involved in tumorigenesis and glaucoma

Ahmed M Alafeefy; Fabrizio Carta; Mariangela Ceruso; Abdul-Malek S Al-Tamimi; Abdulla A Al-Kahtani; Claudiu T Supuran

doi:10.1016/j.bmc.2016.02.011

Development of 3-(4-aminosulphonyl)-phenyl-2-mercapto-3H-quinazolin-4-ones as inhibitors of carbonic anhydrase isoforms involved in tumorigenesis and glaucoma

Bioorg Med Chem. 2016 Mar 15;24(6):1402-7. doi: 10.1016/j.bmc.2016.02.011. Epub 2016 Feb 8.

Authors

Ahmed M Alafeefy¹, Fabrizio Carta², Mariangela Ceruso², Abdul-Malek S Al-Tamimi³, Abdulla A Al-Kahtani⁴, Claudiu T Supuran⁵

Affiliations

¹ DAIS, 11981 Alkharj B.O. 217, Saudi Arabia. Electronic address: alafeefy@hotmail.com.
² Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy.
³ Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, PO Box 173, Alkharj 11942, Saudi Arabia.
⁴ Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, PO Box 173, Alkharj 11942, Saudi Arabia; Chemistry Department, Faculty of Science, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia.
⁵ Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy; Università degli Studi di Firenze, Neurofarba Dept., Section of Pharmaceutical and Nutriceutical Sciences, Via U. Schiff 6, 50019 Sesto Fiorentino (Florence), Italy. Electronic address: claudiu.supuran@unifi.it.

PMID: 26875933
DOI: 10.1016/j.bmc.2016.02.011

Abstract

A series of heterocyclic benzenesulfonamides incorporating 2-mercapto-3H-quinazolin-4-one tails were prepared by condensation of substituted anthranilic acids with 4-isothiocyanato-benzenesulfonamide. These sulfonamides were investigated as inhibitors of the human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms hCA I and II (cytosolic isozymes), as well as hCA IX and XII (trans-membrane, tumor-associated enzymes). They acted as medium potency inhibitors of hCA I (KIs of 81.0-3084 nM), being highly effective as hCA II (KIs in the range of 0.25-10.8 nM), IX (KIs of 3.7-50.4 nM) and XII (KIs of 0.60-52.9 nM) inhibitors. These compounds should thus be of interest as preclinical candidates in pathologies in which the activity of these enzymes should be inhibited, such as glaucoma (CA II and XII as targets) or some tumors in which the activity of three isoforms (CA II, IX and XII) is dysregulated.

Keywords: Carbonic anhydrase; Mercaptan; Quinazoline; Sulfonamides; Tumor-associated isoforms.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / chemistry
Carbonic Anhydrase Inhibitors / pharmacology*
Carbonic Anhydrases / metabolism*
Cell Transformation, Neoplastic / drug effects*
Dose-Response Relationship, Drug
Glaucoma / drug therapy*
Glaucoma / enzymology*
Glaucoma / genetics
Humans
Isoenzymes / antagonists & inhibitors
Isoenzymes / metabolism
Molecular Structure
Quinazolinones / chemical synthesis
Quinazolinones / chemistry
Quinazolinones / pharmacology*
Structure-Activity Relationship
Sulfhydryl Compounds / chemical synthesis
Sulfhydryl Compounds / chemistry
Sulfhydryl Compounds / pharmacology*

Substances

Carbonic Anhydrase Inhibitors
Isoenzymes
Quinazolinones
Sulfhydryl Compounds
Carbonic Anhydrases