Carbonic Anhydrase Inhibition Activities of Schiff’s Bases Based on Quinazoline-Linked Benzenesulfonamide

Human carbonic anhydrase (CA, EC 4.2.1.1) (hCA) isoforms I, II, IX, and XII were investigated for their inhibitory activity with a series of new Schiff’s bases based on quinazoline scaffold <b>4</b>–<b>27</b>. The hCA I isoform was efficiently inhibited by Schiff’s bases <...

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Main Authors: Adel S. El-Azab, Alaa A.-M. Abdel-Aziz, Hazem A. Ghabbour, Silvia Bua, Alessio Nocentini, Hamad M. Alkahtani, Nawaf A. Alsaif, Mohamed H. M. Al-Agamy, Claudiu T. Supuran
Format: Article
Language:English
Published: MDPI AG 2022-11-01
Series:Molecules
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Online Access:https://www.mdpi.com/1420-3049/27/22/7703
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Summary:Human carbonic anhydrase (CA, EC 4.2.1.1) (hCA) isoforms I, II, IX, and XII were investigated for their inhibitory activity with a series of new Schiff’s bases based on quinazoline scaffold <b>4</b>–<b>27</b>. The hCA I isoform was efficiently inhibited by Schiff’s bases <b>4</b>–<b>6</b>, <b>10</b>–<b>19</b>, <b>22</b>–<b>27</b> and had an inhibition constant (Ki) value of 52.8–991.7 nM compared with AAZ (Ki, 250 nM). Amongst the quinazoline derivatives, the compounds <b>2</b>, <b>3</b>, <b>4</b>, <b>10</b>, <b>11</b>, <b>16</b>, <b>18</b>, <b>24</b>, <b>26</b>, and <b>27</b> were proven to be effective hCA II inhibitors, with Ki values of 10.8–52.6 nM, measuring up to AAZ (Ki, 12 nM). Compounds <b>2</b>–<b>27</b> revealed compelling hCA IX inhibitory interest with Ki values of 10.5–99.6 nM, rivaling AAZ (Ki, 25.0 nM). Quinazoline derivatives <b>3</b>, <b>10</b>, <b>11</b>, <b>13</b>, <b>15</b>–<b>19</b>, and <b>24</b> possessed potent hCA XII inhibitory activities with K<sub>I</sub> values of 5.4–25.5 nM vs. 5.7 nM of AAZ. Schiff’s bases <b>7</b>, <b>8</b>, <b>9</b>, and <b>21</b> represented attractive antitumor hCA IX carbonic anhydrase inhibitors (CAIs) with K<sub>I</sub> rates (22.0, 34.8, 49.2, and 45.3 nM, respectively). Compounds <b>5</b>, <b>7</b>, <b>8</b>, <b>9</b>, <b>14</b>, <b>18</b>, <b>19</b>, and <b>21</b> showed hCA I inhibitors on hCA IX with a selectivity index of 22.46–107, while derivatives <b>12</b>, <b>14</b>, and <b>18</b> showed selective hCA I inhibitors on hCA XII with a selectivity profile of 45.04–58.58, in contrast to AAZ (SI, 10.0 and 43.86). Compounds <b>2</b>, <b>5</b>, <b>7</b>–<b>14</b>, <b>19</b>–<b>23</b>, and <b>25</b> showed a selectivity profile for hCA II inhibitors over hCA IX with a selectivity index of 2.02–19.67, whereas derivatives <b>5</b>, <b>7</b>, <b>8</b>, <b>13</b>, <b>14</b>, <b>15</b>, <b>17</b>, <b>20</b>, <b>21</b>, and <b>22</b> showed selective hCA II inhibitors on hCA XII with a selectivity profile of 4.84–26.60 balanced to AAZ (SI, 0.48 and 2.10).
ISSN:1420-3049