S-substituted 2-mercaptoquinazolin-4(3H)-one and 4-ethylbenzensulfonamides act as potent and selective human carbonic anhydrase IX and XII inhibitors
Creators: name: El-Azab, Adel S.
name: Abdel-Aziz, Alaa A.-M.
name: Bua, Silvia
name: Nocentini, Alessio
name: AlSaif, Nawaf A.
name: Alanazi, Mohammed M.
name: El-Gendy, Manal A.
name: Ahmed, Hany E. A.
name: Supuran, Claudiu T.
Publisher: name: Taylor & Francis
Year: 2020
Subjects: subject: Biochemistry
subject: Medicine
subject: Physiology
subject: FOS: Biological sciences
subject: Pharmacology
subject: Biotechnology
subject: Evolutionary Biology
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: 69999 Biological Sciences not elsewhere classified
subject: 19999 Mathematical Sciences not elsewhere classified
subject: FOS: Mathematics
subject: Cancer
subject: Plant Biology
subject: 60506 Virology

description: 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 <b>2–20</b>) towards the isoforms I, II, IX, and XII. hCA Isoforms were effectively inhibited by most of new compounds comparable to those of AAZ. Compounds <b>2</b> and <b>4</b> showed interestingly efficient and selective antitumor (hCA IX and hCA XII) inhibitor activities (K<sub>I</sub>s; 40.7, 13.0, and 8.0, 10.8 nM, respectively). Compounds <b>4</b> and <b>5</b> 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 <b>12–17</b>, and <b>19–20</b> 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 <b>12</b>, <b>14–17</b>, and <b>19</b> 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, <b>17</b> and <b>20</b> and hCAs isoenzymes. Compounds <b>17</b> and <b>20</b>, 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 <b>4</b> and <b>5</b> were found to be selective hCA IX/hCA I and hCA IX/hCA II inhibitors.Compounds <b>4</b> and <b>5</b> were found to be selective hCA XII/hCA I and hCA XII/hCA II inhibitors.Compounds <b>12</b>–<b>17</b>, <b>19</b>, and <b>20</b> were found to be selective hCA IX/hCA I and hCA IX/hCA II inhibitors.Compounds <b>12</b>, <b>14</b>–<b>17</b>, <b>19</b> were found to be selective hCA XII/hCA I and hCA XII/hCA II inhibitors. Graphical AbstractCompounds <b>4</b> and <b>5</b> are selective hCA IX and XII inhibitors over hCA I (selectivity ratios of 95, 23, and 24, 5.8, respectively) and hCA II (selectivity ratios of 70, 17, and 44, 10 respectively). Compounds <b>12–17</b>, and <b>19–20</b> are selective hCA IX inhibitors over hCA I (selectivity ratios of 27-195) and hCA II (selectivity ratios of 3.2-19). Compounds <b>12</b>, <b>14–17</b> and <b>19</b> are also selective hCA XII inhibitors over hCA I (selectivity ratios of 48-158) and hCA II (selectivity ratios of 5.4-31). Quinazoline-linked ethylbenzenesulfonamides inhibiting CA were synthesised. The new molecules potently inhibited the hCA isoforms I, II, IV, and IX. Compounds <b>4</b> and <b>5</b> were found to be selective hCA IX/hCA I and hCA IX/hCA II inhibitors. Compounds <b>4</b> and <b>5</b> were found to be selective hCA XII/hCA I and hCA XII/hCA II inhibitors. Compounds <b>12</b>–<b>17</b>, <b>19</b>, and <b>20</b> were found to be selective hCA IX/hCA I and hCA IX/hCA II inhibitors. Compounds <b>12</b>, <b>14</b>–<b>17</b>, <b>19</b> were found to be selective hCA XII/hCA I and hCA XII/hCA II inhibitors. Compounds <b>4</b> and <b>5</b> are selective hCA IX and XII inhibitors over hCA I (selectivity ratios of 95, 23, and 24, 5.8, respectively) and hCA II (selectivity ratios of 70, 17, and 44, 10 respectively). Compounds <b>12–17</b>, and <b>19–20</b> are selective hCA IX inhibitors over hCA I (selectivity ratios of 27-195) and hCA II (selectivity ratios of 3.2-19). Compounds <b>12</b>, <b>14–17</b> and <b>19</b> are also selective hCA XII inhibitors over hCA I (selectivity ratios of 48-158) and hCA II (selectivity ratios of 5.4-31).