Design and Discovery of New Dual Carbonic Anhydrase IX and VEGFR-2 Inhibitors Based on the Benzenesulfonamide-Bearing 4-Thiazolidinones/2,4-Thiazolidinediones Scaffold.

Autor: Zengin M; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey., Unsal Tan O; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey., Sabuncuoglu S; Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey., Arafa RK; Drug Design and Discovery Lab, Zewail City of Science and Technology, Cairo, Egypt.; Biomedical Sciences Program, Zewail City of Science and Technology, University of Science and Technology, Cairo, Egypt., Balkan A; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey.
Jazyk: angličtina
Zdroj: Drug development research [Drug Dev Res] 2024 Dec; Vol. 85 (8), pp. e70030.
DOI: 10.1002/ddr.70030
Abstrakt: Dual-targeting drug design has become a popular approach in investigating and developing potent anticancer agents. In this regard, carbonic anhydrase (CAIX) and vascular endothelial growth factor receptor (VEGFR-2) are emerging as highly effective targets in the battle against cancer. In the present study, two series of 4-thiazolidinones/2,4-thiazolidinediones carrying 2-methylbenzenesulfonamide derivatives were designed and synthesized as potential dual CAIX/VEGFR-2 inhibitors. All the target compounds were evaluated against CAIX enzyme compared to dorzolamide and acetazolamide, subsequently the most potent CAIX inhibitors (3a, 3b, 3o, 6d, 6g, and 6i) were selected to evaluate their inhibitory activity against VEGFR-2 using sorafenib as a reference drug. These compounds were also evaluated against MCF-7 breast cancer cells and the murine fibroblast 3T3 cell line. According to the results, 3b (CAIX IC 50  = 0.035 µM, VEGFR-2 IC 50  = 0.093 µM) and 6i (CAIX IC 50  = 0.041 µM, VEGFR-2 IC 50  = 0.048 µM) emerged the most potent compounds against CAIX and VEGFR-2. Furthermore, docking studies of selected compounds were performed with the CAIX and the tyrosine kinase domain of VEGFR-2 to comprehend the ligand-binding interactions. Physicochemical predictions were examined using in silico techniques. In conclusion, these scaffolds present promising leads and furnish promising chemical backbones for the design of potent dual CAIX and VEGFR-2 inhibitors.b.
(© 2024 Wiley Periodicals LLC.)
Databáze: MEDLINE
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