New quinoline and isatin derivatives as apoptotic VEGFR-2 inhibitors: design, synthesis, anti-proliferative activity, docking, ADMET, toxicity, and MD simulation studies

Eslam B Elkaeed; Mohammed S Taghour; Hazem A Mahdy; Wagdy M Eldehna; Nehal M El-Deeb; Ahmed M Kenawy; Bshra A Alsfouk; Mohammed A Dahab; Ahmed M Metwaly; Ibrahim H Eissa; Mohamed A El-Zahabi

doi:10.1080/14756366.2022.2110869

New quinoline and isatin derivatives as apoptotic VEGFR-2 inhibitors: design, synthesis, anti-proliferative activity, docking, ADMET, toxicity, and MD simulation studies

J Enzyme Inhib Med Chem. 2022 Dec;37(1):2191-2205. doi: 10.1080/14756366.2022.2110869.

Authors

Affiliations

¹ Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh, 13713, Saudi Arabia.
² Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.
³ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.
⁴ Biopharmaceutical Products Research Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Alexandria, Egypt.
⁵ Pharmaceutical and Fermentation Industries Development Center, City of Scientific Research and Technological Applications (SRTA city), Alexandria, Egypt.
⁶ Nucleic Acids Research Department, Genetic Engineering and Biotechnology Research Institute. City of Scientific Research and Technological Applications (SRTA-City), Alexandria, Egypt.
⁷ Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.
⁸ Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.

Abstract

New quinoline and isatin derivatives having the main characteristics of VEGFR-2 inhibitors was synthesised. The antiproliferative effects of these compounds were estimated against A549, Caco-2, HepG2, and MDA-MB-231. Compounds 13 and 14 showed comparable activities with doxorubicin against the Caco-2 cells. These compounds strongly inhibited VEGFR-2 kinase activity. The cytotoxic activities were evaluated against Vero cells. Compound 7 showed the highest value of safety and selectivity. Cell migration assay displayed the ability of compound 7 to prevent healing and migration abilities in the cancer cells. Furthermore, compound 7 induced apoptosis in Caco-2 through the expressive down-regulation of the apoptotic genes, Bcl2, Bcl-xl, and Survivin, and the upregulation of the TGF gene. Molecular docking against VEGFR-2 emerged the interactions of the synthesised compounds in a similar way to sorafenib. Additionally, seven molecular dynamics simulations studies were applied and confirmed the stability of compound 13 in the active pocket of VEGFR-2 over 100 ns.

Keywords: MD simulations; VEGFR-2; anticancer; apoptosis; cell cycle analysis; docking; gene expression; isatin derivatives; quinoline derivatives.

MeSH terms

Animals
Antineoplastic Agents* / pharmacology
Caco-2 Cells
Cell Proliferation
Chlorocebus aethiops
Drug Screening Assays, Antitumor
Humans
Isatin* / pharmacology
Molecular Docking Simulation
Molecular Structure
Protein Kinase Inhibitors / pharmacology
Quinolines* / pharmacology
Structure-Activity Relationship
Vascular Endothelial Growth Factor Receptor-2
Vero Cells

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Quinolines
Isatin
Vascular Endothelial Growth Factor Receptor-2

Grants and funding

This research was funded by Princess Nourah bint Abdulrahman University Researchers Supporting Project number [PNURSP2022R142], Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.