1,3,4-Oxadiazole-naphthalene hybrids as potential VEGFR-2 inhibitors: design, synthesis, antiproliferative activity, apoptotic effect, and in silico studies

Mohamed Hagras; Marwa A Saleh; Rogy R Ezz Eldin; Abdelrahman A Abuelkhir; Emad Gamil Khidr; Ahmed A El-Husseiny; Hesham A El-Mahdy; Eslam B Elkaeed; Ibrahim H Eissa

doi:10.1080/14756366.2021.2015342

1,3,4-Oxadiazole-naphthalene hybrids as potential VEGFR-2 inhibitors: design, synthesis, antiproliferative activity, apoptotic effect, and in silico studies

J Enzyme Inhib Med Chem. 2022 Dec;37(1):380-396. doi: 10.1080/14756366.2021.2015342.

Authors

Mohamed Hagras¹, Marwa A Saleh², Rogy R Ezz Eldin³, Abdelrahman A Abuelkhir¹, Emad Gamil Khidr⁴, Ahmed A El-Husseiny⁴, Hesham A El-Mahdy⁴, Eslam B Elkaeed⁵, Ibrahim H Eissa⁶

Affiliations

¹ Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.
² Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt.
³ Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Port Said University, Port Said, Egypt.
⁴ Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.
⁵ Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh, Saudi Arabia.
⁶ Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.

Abstract

In the current work, some 1,3,4-oxadiazole-naphthalene hybrids were designed and synthesised as VEGFR-2 inhibitors. The synthesised compounds were evaluated in vitro for their antiproliferative activity against two human cancer cell lines namely, HepG-2 and MCF-7. Compounds that exhibited promising cytotoxicity (5, 8, 15, 16, 17, and 18) were further evaluated for their VEGFR-2 inhibitory activities. Compound 5 showed good antiproliferative activity against both cell lines and inhibitory effect on VEGFR-2. Besides, it induced apoptosis by 22.86% compared to 0.51% in the control (HepG2) cells. This apoptotic effect was supported by a 5.61-fold increase in the level of caspase-3 compared to the control cells. Moreover, it arrested the HepG2 cell growth mostly at the Pre-G1 phase. Several in silico studies were performed including docking, ADMET, and toxicity studies to predict binding mode against VEGFR-2 and to anticipate pharmacokinetic, drug-likeness, and toxicity of the synthesised compounds.

Keywords: 1,3,4-oxadiazole; Anticancer; VEGFR-2 inhibitors; apoptosis; docking.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Proliferation / drug effects
Cells, Cultured
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Humans
Molecular Docking Simulation
Molecular Structure
Naphthalenes / chemical synthesis
Naphthalenes / chemistry
Naphthalenes / pharmacology*
Oxadiazoles / chemical synthesis
Oxadiazoles / chemistry
Oxadiazoles / pharmacology*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

Antineoplastic Agents
Naphthalenes
Oxadiazoles
Protein Kinase Inhibitors
KDR protein, human
Vascular Endothelial Growth Factor Receptor-2

Grants and funding

The authors extend their appreciation to the Research center at AlMaarefa University for funding this work under TUMA project number "TUMA-2021-4".