Exploring structure-activity relationship of S-substituted 2-mercaptoquinazolin-4(3H)-one including 4-ethylbenzenesulfonamides as human carbonic anhydrase inhibitors

• Published in: Journal of enzyme inhibition and medicinal chemistry 2020-01, Vol.35 (1), p.598-609
• Main Authors: El-Azab, Adel S., Abdel-Aziz, Alaa A.-M., Ahmed, Hany E. A., Bua, Sivia, Nocentini, Alessio, AlSaif, Nawaf A., Obaidullah, Ahmad J., Hefnawy, Mohamed M., Supuran, Claudiu T.
• Format: Article
• Language: English
• Subjects: Arthritis; Carbonic Anhydrase Inhibitors - chemical synthesis; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase Inhibitors - pharmacology; Carbonic anhydrases; Carbonic Anhydrases - metabolism; Dose-Response Relationship, Drug; Enzymes; Epilepsy; Glaucoma; Humans; inhibition; Isoenzymes - antagonists & inhibitors; Isoenzymes - metabolism; Isoforms; Metalloenzyme; Molecular Docking Simulation; molecular docking study; Molecular Structure; NMR; Nuclear magnetic resonance; Pharmaceutical sciences; Pharmacy; Quinazolines - chemical synthesis; Quinazolines - chemistry; Quinazolines - pharmacology; quinazolinone; Research Paper; selectivity; Structure-Activity Relationship; sulphonamide; Tumors
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2020.1722121

Inhibitory action of newly synthesised 4-(2-(2-substituted-thio-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamides compounds 2-13 against human carbonic anhydrase (CA, EC 4.2.1.1) (hCA) isoforms I, II, IX, and XII, was evaluated. hCA I was efficiently inhibited by compounds 2-13 with inhibition constants (K I s) ranging from 57.8-740.2 nM. Compounds 2, 3, 4, and 12 showed inhibitory action against hCA II with K I s between 6.4 and 14.2 nM. CA IX exhibited significant sensitivity to inhibition by derivatives 2-13 with K I values ranging from 7.1 to 93.6 nM. Compounds 2, 3, 4, 8, 9, and 12 also exerted potent inhibitory action against hCA XII (K I s ranging from 3.1 to 20.2 nM). Molecular docking studies for the most potent compounds 2 and 3 were conducted to exhibit the binding mode towards hCA isoforms as a promising step for SAR analyses which showed similar interaction with co-crystallized ligands. As such, a subset of these mercaptoquinazolin-4(3H)-one compounds represented interesting leads for developing new efficient and selective carbonic anhydrase inhibitors (CAIs) for the management of a variety of diseases including glaucoma, epilepsy, arthritis and cancer.