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Design and synthesis of some new benzoylthioureido benzenesulfonamide derivatives and their analogues as carbonic anhydrase inhibitors.

ABSTRACT: The present investigation reports the design and synthesis of three series of benzoylthioureido derivatives bearing either benzenesulfonamide 7a-f, benzoic acid 8a-f or ethylbenzoate 9a-f moieties. The synthesised compounds were screened for their carbonic anhydrase inhibitory activity (CAI) against four isoforms hCA I, II, IX, and XII. Compounds 7a, 7b, 7c, and 7f exhibited a potent inhibitory activity towards hCAI (K_is = 58.20, 56.30, 33.00, and 43.00 nM), respectively compared to acetazolamide (AAZ) and SLC-0111 (K_is = 250.00 and 5080.00 nM). Compounds 7a, 7b, 7c, 7e, and 7f elicited selectivity over h CA II (K_is = 2.50, 2.10, 56.60,39.60 and 39.00 nM) respectively, relative to AAZ and SLC-0111(K_is = 12.10 and 960.00 nM). Also, compounds 7c, 7f, and 9e displayed selectivity against the tumour-associated isoform hCA IX (K_is = 31.20, 30.00 and 29.00 nM) respectively, compared to AAZ and SLC-0111 (K_is = 25.70 and 45.00 nM). Additionally, compounds 8a and 8f revealed a moderate to superior selectivity towards hCAXII (K_is = 17.00 and 11.00 nM) relative to AAZ and SLC-0111(K_is = 5.70 and 45.00 nM). Molecular docking and ADME prediction studies were performed on the most active compounds to shed light on their interaction with the hot spots of the active site of CA isoforms, in addition to prediction of their pharmacokinetic and physicochemical properties.

SUBMITTER: Oudah KH

PROVIDER: S-EPMC9621292 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Design and synthesis of some new benzoylthioureido benzenesulfonamide derivatives and their analogues as carbonic anhydrase inhibitors.

Oudah Khulood H KH Mahmoud Walaa R WR Awadallah Fadi M FM Taher Azza T AT Abbas Safinaz E-S SE Allam Heba Abdelrasheed HA Vullo Daniela D Supuran Claudiu T CT

Journal of enzyme inhibition and medicinal chemistry 20231201 1

The present investigation reports the design and synthesis of three series of benzoylthioureido derivatives bearing either benzenesulfonamide 7a-f, benzoic acid 8a-f or ethylbenzoate 9a-f moieties. The synthesised compounds were screened for their carbonic anhydrase inhibitory activity (CAI) against four isoforms hCA I, II, IX, and XII. Compounds 7a, 7b, 7c, and 7f exhibited a potent inhibitory activity towards hCAI (Kis = 58.20, 56.30, 33.00, ...[more]

PMID: 36305274

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Project description:Changes in gene expression cause uncontrolled cell proliferation and consequently tumor hypoxia. The tumor cells shift their metabolism to anaerobic glycolysis with a significant modification in pH. Therefore, an over expression of carbonic anhydrase IX (CA IX) genes was detected in many solid tumors. Accordingly, selective inhibition of CA IX can be a useful target for discovering novel antiproliferative agents. The present study described the synthesis of new aryl thiazolone-benzenesulfonamides 4a-j as well as their carbonic anhydrase IX inhibitory effect. All the designed derivatives were evaluated for their anti-proliferative activity against triple-negative breast cancer cell line (as MDA-MB-231) and another breast cancer cell line (MCF-7) in addition to normal breast cell line MCF-10A. Compounds 4b-c, 4e, 4g-h showed significant inhibitory effect against both cancer cell lines at concentration ranges from 1.52-6.31 μM, with a high selectivity against breast cancer cell lines ranges from 5.5 to 17.5 times. Moreover, three sulfonamides derivatives 4e, 4g and 4h showed excellent enzyme inhibition against CA IX with IC50 10.93-25.06 nM and against CA II with IC50 1.55-3.92 μM that revealed their remarkable selectivity for CA IX over CA II. Additionally, 4e was able to induce apoptosis in MDA-MB-231 with a significant increase in the annexin V-FITC percent by 22 fold as compared with control. Cellular uptake on MDA-MB-231 cell lines were carried out using HPLC method on the three active compounds (4e, 4g and 4h). On the other hand inhibition of one or more CAs present in bacteria was reported to interfere with bacterial growth. So, the new benzenesulfonamides were evaluated against their antibacterial and anti-biofilm activities. Analogues 4e, 4g and 4h exhibited significant inhibition at 50 μg mL-1 concentration with 80.69%, 69.74% and 68.30% against S. aureus compared to the positive control CIP which was 99.2%, while compounds 4g and 4h showed potential anti-biofilm inhibition 79.46% and 77.52% against K. pneumonia. Furthermore, the designed compounds were docked into CA IX (human) protein (PDB ID: 5FL6) and molecular modeling studies revealed favorable binding interactions for the active inhibitors. Finally, the predictive ADMET studies showed that, compounds 4e, 4g and 4h possessed promising pharmacokinetic properties.

Dataset Information

Design and synthesis of some new benzoylthioureido benzenesulfonamide derivatives and their analogues as carbonic anhydrase inhibitors.

Publications

Design and synthesis of some new benzoylthioureido benzenesulfonamide derivatives and their analogues as carbonic anhydrase inhibitors.

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