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

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

doi:10.1080/14756366.2020.1722121

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 (KIs) ranging from 57.8–740.2 nM. Compounds 2, 3, 4, and 12 showed inhibitory action against hCA II with KIs between 6.4 and 14.2 nM. CA IX exhibited significant sensitivity to inhibition by derivatives 2–13 with KI 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 (KIs 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.

Highlights

Carbonic anhydrases (CAs; EC 4.2.1.1) constitute the superfamily of metalloenzymes catalysing the CO2 hydration/dehydration reaction
CAs are classified into eight genetically distinct families, named a, b, c, d, f, g, Õ, and i-CAs1,2. 15 a-class isoenzymes have been detected in humans (h) and are sorted into four different subsets depending on their subcellular localisation: CA I, II, III, VII, VIII, X, XI, XIII are cytosolic proteins, CA VA and VB are present in the mitochondrial matrix, CA VI is a secreted enzyme, CA IV is a glycosylphosphatidylinositol (GPI)-anchored protein and CA IX, XII, and XIV are trans-membrane isoforms1–3. hCAs are spread in the human body and are implicated in a plethora of essential physiological processes
CA II is the most physiologically relevant isoform and is implicated in disorders such as cerebral oedema, glaucoma, and epilepsy. It is off-target like CA I, when targeting tumours where CA IX and XII are overexpressed and represent validated targets to combat the growth of both primary tumours and metastasis4

Summary

Introduction

Carbonic anhydrases (CAs; EC 4.2.1.1) constitute the superfamily of metalloenzymes catalysing the CO2 hydration/dehydration reaction. CA II is the most physiologically relevant isoform and is implicated in disorders such as cerebral oedema, glaucoma (such as CA XII), and epilepsy. Yl)ethyl)benzenesulfonamide (1, Figure 1) showed effective inhibitory activity against a subset of hCA isoforms with subnanomolar inhibition constants. Oxo-3,4-dihydroquinazolin-2-yl)thio)-N-(4-sulfamoylphenethyl)amides (A, Figure 1) showed nanomolar inhibitory action against a panel of hCAs39. 4(3H)quinazolinon-3-yl)-benzenesulfonamide (C, Figure 1) were reported to exert potent inhibitory effect against CA I, II, IX and XII41,42. As observed from SAR analysis of the reported C derivatives (Figure 1), it is thought to add an ethyl linker between sulphonamide part and quinazoline scaffold and alkylation of free SH. We report the synthesis of a new series of 4(2-(2-(substituted-thio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamide compounds (2–13, Figure 1) and evaluated their inhibitory action against four pharmacologically relevant hCA isoforms, I, II, IX, and XII

Chemistry

CA inhibition

CA inhibitory activity

Molecular docking studies

Conclusions

Findings

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