Design and synthesis of thiazolidine-2,4-diones hybrids with 1,2-dihydroquinolones and 2-oxindoles as potential VEGFR-2 inhibitors: in-vitro anticancer evaluation and in-silico studies

Mohammed S Taghour; Hazem Elkady; Wagdy M Eldehna; Nehal M El-Deeb; Ahmed M Kenawy; Eslam B Elkaeed; Aisha A Alsfouk; Mohamed S Alesawy; Ahmed M Metwaly; Ibrahim H Eissa

doi:10.1080/14756366.2022.2085693

Design and synthesis of thiazolidine-2,4-diones hybrids with 1,2-dihydroquinolones and 2-oxindoles as potential VEGFR-2 inhibitors: in-vitro anticancer evaluation and in-silico studies

J Enzyme Inhib Med Chem. 2022 Dec;37(1):1903-1917. doi: 10.1080/14756366.2022.2085693.

Authors

Affiliations

¹ Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.
² Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.
³ School of Biotechnology, Badr University in Cairo, Badr City, Cairo, Egypt.
⁴ Biopharmaceutical Products Research Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Alexandria, Egypt.
⁵ Nucleic Acids Research Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Alexandria, Egypt.
⁶ Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh, Saudi Arabia.
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

A thiazolidine-2,4-dione nucleus was molecularly hybridised with the effective antitumor moieties; 2-oxo-1,2-dihydroquinoline and 2-oxoindoline to obtain new hybrids with potential activity against VEGFR-2. The cytotoxic effects of the synthesised derivatives against Caco-2, HepG-2, and MDA-MB-231 cell lines were investigated. Compound 12a was found to be the most potent candidate against the investigated cell lines with IC₅₀ values of 2, 10, and 40 µM, respectively. Furthermore, the synthesised derivatives were tested in vitro for their VEGFR-2 inhibitory activity showing strong inhibition. Moreover, an in vitro viability study against Vero non-cancerous cell line was investigated and the results reflected a high safety profile of all tested compounds. Compound 12a was further investigated for its apoptotic behaviour by assessing the gene expression of four genes (Bcl2, Bcl-xl, TGF, and Survivin). Molecular dynamic simulations authenticated the high affinity, accurate binding, and perfect dynamics of compound 12a against VEGFR-2.

Keywords: 2-Oxo-1,2-dihydroquinoline; 2-Oxoindoline; Apoptosis; Thiazolidine-2,4-dione; VEGFR-2 inhibitors; anticancer.

MeSH terms

Antineoplastic Agents* / chemistry
Caco-2 Cells
Cell Proliferation
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Molecular Docking Simulation
Molecular Structure
Oxindoles
Protein Kinase Inhibitors / pharmacology
Structure-Activity Relationship
Thiazolidines / pharmacology
Vascular Endothelial Growth Factor Receptor-2*

Substances

Antineoplastic Agents
Oxindoles
Protein Kinase Inhibitors
Thiazolidines
2-oxindole
Vascular Endothelial Growth Factor Receptor-2

Grants and funding

This research was funded by Princess Nourah bint Abdulrahman University Researchers Supporting Project number [PNURSP2022R116], Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia. The authors extend their appreciation to the Research Center at AlMaarefa University for funding this work.