Discovery of new quinoline and isatine derivatives as potential VEGFR-2 inhibitors: design, synthesis, antiproliferative, docking and MD simulation studies

Abstract

A new set of quinoline and isatine derivatives were synthesized as antiangiogenic VEGFR-2 inhibitors. On a biological level, the in vitro ability of the obtained candidates to inhibit VEGFR-2 was found to be strong with IC₅₀ values in the range of 76.64–175.50 nM. To investigate the cytotoxicity and safety, all compounds were tested against a panel of four cancer cell lines (A549, Caco2, HepG2 and MDA) as well as two normal cell lines (Vero and WI-38). Interestingly, compound 12 exhibited noticeable cytotoxicity against A549, Caco2 and MDA with IC₅₀ values of 5.40, 0.58 and 0.94 µM, respectively. These results were better and comparable to that of doxorubicin (0.70, 0.82 and 0.90 µM, respectively) with more than three folds higher selectivity index against the Caco2 cell lines. Compound 9 prevented the healing of the cancer cells at a low concentration. Also, the compound’s potential to induce programmed cell death in Caco-2 was proved through the significant down regulating of the expression of Bcl2, Bcl-xl and Survivin in addition to the slight upregulation of the TGF-β gene. The cell cycle analysis indicated that compound 9 arrested the Caco-2 cells in the G2/M phase. Interestingly, the molecular docking studies against VEGFR-2 revealed the correct binding of the targeted compounds similar to sorafenib. Furthermore, MD experiments validated the binding of compound 12 with VEGFR-2 over 100 ns, as well as MM-PBSA analysis that confirmed the precise binding with optimum energy. Finally, ADMET analysis showed the general drug-likeness and confirmed the safety of the tested compounds.

Communicated by Ramaswamy H. Sarma

Keywords:

• Anti-cancer
• docking
• VEGFR-2
• MD simulation
• quinoline
• isatine

Disclosure statement

There is not any conflict of interest.

Additional information

Funding

This research was funded by Princess Nourah bint Abdulrahman University Researchers Supporting Project number (P NURSP2023R142), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia. The authors extend their appreciation to the Research Center at AlMaarefa University for funding this work