Novel sulfonamide-tethered Schiff bases as anti-proliferative agents with VEGFR-2 inhibitory activity: Synthesis, biological assessment, and molecular dynamic simulations

• Published in: Journal of molecular structure 2024-08, Vol.1309, p.138148, Article 138148
• Main Authors: Shaldam, Moataz A., Abdulla, Maha-Hamadien, Angeli, Andrea, Hefny, Salma M., El-labbad, Eman M., Obeed, Abdullah Bin, Alhassan, Noura S., Supuran, Claudiu T., Eldehna, Wagdy M., Tawfik, Haytham O.
• Format: Article
• Language: English
• Subjects: Apoptotic markers; Breast cancer; Carbonic anhydrases; In silico studies; Synthesis; VEGFR-2 inhibitors
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2024.138148

•New sulfonamide-tethered Schiff bases were developed as potential CA IX and VEGFR-2 inhibitors.•The anticancer activity was tested using the MCF7 and HepG2 cancer cell lines.•The potential inhibitory activities against cancer-related CA IX and VEGFR-2 were evaluated.•Target Schiff bases effectively inhibited VEGFR-2 kinase, whereas they failed to inhibit CA.•A molecular modeling study, including docking and molecular dynamics, was performed. Schiff bases tethered with sulfonamide functionality (6a-l) are reported as potential anticancer agents and apoptotic inducers. The anti-proliferative activities of the tested Schiff bases were evaluated against breast (MCF7) and hepatocellular (HepG2) cancer cells. Additionally, their potential activity against cancer-related carbonic anhydrase (CA) isoforms IX and XII was assessed, and VEGFR-2, as enzyme targets. All the tested molecules displayed good anticancer activities against both cancer cells, with IC50 values ranging from 90 nM to 6.11 µM. The most effective compounds were unable to inhibit CA isoforms, which may be attributed to the bulkiness of the methoxy group, but they had a strong inhibitory effect on VEGFR-2. Moreover, Schiff bases 6i and 6j effectively boosted HepG2 cells apoptosis by around 23 and 19 times, respectively. In the pre-G1 phase, both compounds exhibited similar cell-cycle arrest behavior. Finally, the effects of 6i and 6j on the apoptotic markers caspase-3, Bcl-2, and Bax, were explored. In silico studies assessed drug-likeness and pharmacokinetics properties and the binding mode and stability.