S-substituted 2-mercaptoquinazolin-4(3H)-one and 4-ethylbenzensulfonamides act as potent and selective human carbonic anhydrase IX and XII inhibitors

Abstract

We evaluated the hCA (CA, EC 4.2.1.1) inhibitory activity of novel 4-(2-(2-substituted-thio-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamides (compounds 2-20) towards the isoforms I, II, IX, and XII. hCA Isoforms were effectively inhibited by most of new compounds comparable to those of AAZ. Compounds 2 and 4 showed interestingly efficient and selective antitumor (hCA IX and hCA XII) inhibitor activities (K I s; 40.7, 13.0, and 8.0, 10.8 nM, respectively). Compounds 4 and 5 showed selective hCA IX inhibitory activity over hCA I (SI; 95 and 24), hCA IX/hCA II (SI; 23 and 5.8) and selective hCA XII inhibitory activity over hCA I (SI; 70 and 44), hCA XII/hCA II, (SI; 17 and 10) respectively compared to AAZ. Compounds 12-17, and 19-20 showed selective inhibitory activity towards hCA IX over hCA I and hCA II, with selectivity ranges of 27-195 and 3.2-19, respectively, while compounds 12, 14-17, and 19 exhibited selective inhibition towards hCA XII over hCA I and hCA II, with selectivity ratios of 48-158 and 5.4-31 respectively, compared to AAZ. Molecular docking analysis was carried out to investigate the selective interactions among the most active derivatives, 17 and 20 and hCAs isoenzymes. Compounds 17 and 20, which are highly selective CA IX and XII inhibitors, exhibited excellent interaction within the putative binding site of both enzymes, comparable to the co-crystallized inhibitors. HIGHLIGHTSQuinazoline-linked ethylbenzenesulfonamides inhibiting CA were synthesised. The new molecules potently inhibited the hCA isoforms I, II, IV, and IX. Compounds 4 and 5 were found to be selective hCA IX/hCA I and hCA IX/hCA II inhibitors. Compounds 4 and 5 were found to be selective hCA XII/hCA I and hCA XII/hCA II inhibitors. Compounds 12-17, 19, and 20 were found to be selective hCA IX/hCA I and hCA IX/hCA II inhibitors. Compounds 12, 14-17, 19 were found to be selective hCA XII/hCA I and hCA XII/hCA II inhibitors.

Targeting carbonic anhydrase IX and XII isoforms with small molecule inhibitors and monoclonal antibodies

“…These include sulfonamido carboranes 134 , 135 , benzenesulfonamides incorporating 1,3,4-oxadiazole hybrids 136 , benzimidazole derivatives 137 , 7-Acylamino-3H-1,2-benzoxathiepine 2,2-dioxides 138 , aryl derivatives of 3H-1,2-benzoxathiepine 2,2-dioxide 139 , S-substituted 2-mercaptoquinazolin-4(3H)-ones and 4-ethylbenzensulfonamides 140 , aryl selenols 141 , sulfocoumarins and coumarin derivatives 142–145 , coumarin-thiourea hybrids 146 , phenols, polyamines, carboxylates 147 , epacadostat 148 , pyridinium derivatives of 3-aminobenzenesulfonamide and sulfonamides containing various nitrogenous bases 11 , 149 , 150 and short peptide-constructed nanofibers 151 .…”

Recent Advances on Quinazoline Derivatives: A Potential Bioactive Scaffold in Medicinal Chemistry

“…Quinazoline derivatives bearing benzene sulfonamides moieties were prepared and tested for antitumor activity by El-Azab et al [30]. Synthesized compounds (Table 2, Compound 5) were found most potent against carbonic anhydrase (CA) inhibitory activity.…”

Application of Deep Eutectic Solvents in the Synthesis of Substituted 2-Mercaptoquinazolin-4(3H)-Ones: A Comparison of Selected Green Chemistry Methods

“…The keto functionality may be present on the second, fourth, or both carbon atoms of the quinazoline nucleus (Figure 1) [1]. Exceptional biological activities of quinazolinone derivatives have been demonstrated in previous studies investigating their antibacterial [2], antitumor [3], anticonvulsant [4] and anti-inflammatory [5] and enzyme inhibitory activity [6,7]. These compounds have also Molecules 2022, 27, 558 2 of 19 been found to act via various targets such as tubulin [8], dihydrofolate reductase [9], histone deacetylase [10], COX-1/COX-2 and 15-LOX [11].…”