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

Adel S El-Azab; Alaa A-M Abdel-Aziz; Hany E A Ahmed; Sivia Bua; Alessio Nocentini; Nawaf A AlSaif; Ahmad J Obaidullah; Mohamed M Hefnawy; Claudiu T Supuran

doi:10.1080/14756366.2020.1722121

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

J Enzyme Inhib Med Chem. 2020 Dec;35(1):598-609. doi: 10.1080/14756366.2020.1722121.

Authors

Adel S El-Azab¹, Alaa A-M Abdel-Aziz¹, Hany E A Ahmed^{2

3}, Sivia Bua⁴, Alessio Nocentini⁴, Nawaf A AlSaif¹, Ahmad J Obaidullah¹, Mohamed M Hefnawy¹, Claudiu T Supuran⁴

Affiliations

¹ Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
² Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo, Egypt.
³ Pharmacognosy and Pharmaceutical Chemistry Department, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah, Saudi Arabia.
⁴ Department of Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Florence, Italy.

Abstract

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_Is) ranging from 57.8-740.2 nM. Compounds 2, 3, 4, and 12 showed inhibitory action against hCA II with K_Is 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_Is 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.

Keywords: Metalloenzyme; inhibition; molecular docking study; quinazolinone; selectivity; sulphonamide.

MeSH terms

Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / chemistry
Carbonic Anhydrase Inhibitors / pharmacology*
Carbonic Anhydrases / metabolism*
Dose-Response Relationship, Drug
Humans
Isoenzymes / antagonists & inhibitors
Isoenzymes / metabolism
Molecular Docking Simulation
Molecular Structure
Quinazolines / chemical synthesis
Quinazolines / chemistry
Quinazolines / pharmacology*
Structure-Activity Relationship

Substances

Carbonic Anhydrase Inhibitors
Isoenzymes
Quinazolines
Carbonic Anhydrases

Grants and funding

The authors extend their appreciation to the Deanship of Scientific Research at King Saud University for funding the work through the research group project No. RG-1435-046.