الفهرس 
Synthesis and carbonic anhydrase inhibitory activity of some new sulfonamide based derivatives
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Abstract
The present study describes the design, synthesis and carbonic anhydrase inhibitory activity of eighteen benzoylthioureid
and their analogues VIIIa-f and IXa-f using replacement and elongation tail strategy of SLC-0111 aiming to obtain new derivatives with increased potency and selectivity towards carbonic anhydrase enzyme.
The synthesized compounds were assessed as carbonic anhydrase inhibitors against four isoforms hCA I, II, IX, and XII.
Surprisingly, the benzenesulfonamide derivatives VII were more selective towards hCA I and hCA II rather than tumor associated isoforms hCA IX and hCA XII. Four compounds VIIa, VIIb, VIIc and VIIf exhibited a superior inhibition on hCA I. In addition, compounds VIIa and VIIb displayed their superior selectivity over hCA II. Meanwhile, compounds VIIc and VIIf elicited a remarkable inhibition towards hCA IX. The benzenesulfonamide series VIIa-f did not demonstrate any significant inhibition against hCA XII.
Unfortunately, replacement of (SO2NH2) with its (COOH) bioisostere did not show the expected significant CA inhibition, except compound VIIIa and VIIIf that display selectivity towards hCA XII.
The ethyl carboxylate analogues IXb and IXc showed a good inhibitory activity against hCA II, whereas IXe elicited a remarkable inhibition towards hCA IX. The ethyl carboxylate IXa-f lacked the inhibitory activity against hCA I and hCA XII.
The anticancer activity as GI% on a panel of 60 cell lines revealed that the ethyl carboxylate derivatives IXb and IXc are the most potent ones against some of the tested cell lines. Compound IXb showed a GI% (70.11-75.90) against leukemia (CCRF-CEM, K-562 and MOLT-4), colon cancer (HCT-15), melanoma (SK-MEL-5) and breast cancer (MCF-7, T-47D), whereas, IXc displayed a superior GI% (97.73) against CNS cancer cell line U-251, in addition to Ovarian cancer cell line OVACAR-4 (72.22%) and OVACAR-8 (71.06%).
Remarkably, compounds VIIc, VIIf, VIIIa and VIIIf showing a significant CA inhibition against tumor associated isoforms hCA IX and hCA XII did not demonstrate any noticeable growth inhibition against 60 cancer cell lines.
CDK2 inhibitory activity of IXb was in submicromolar concentration (IC50 = 0.875 µM) compared to roscovitine (IC50 = 0.7118µM).
Simulation of docking for the most active compounds VIIa, VIIb, VIIc, VIIf, VIIIa, VIIIf and IXe based on their docking binding patterns and scores, predicted their binding mode and binding affinity to the hCA I, II, IX, and XII active sites and explained their selectivity. Moreover, compounds VIIIa and IXe have favorable pharmacokinetic characteristics in addition to exhibiting significant CA inhibitory activity towards CA IX and XII respectively.
Compounds VIIa and VIIb is considered as promising candidates to develop new hCA II inhibitors, whereas IXb and IXc can be planned to be a lead for emerging new hCA XII inhibitor.