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.
Mohamed Hagras  1 ,  Marwa A Saleh  2 ,  Rogy R Ezz Eldin  3 ,  Abdelrahman A Abuelkhir  1 ,  Emad Gamil Khidr  4 ,  Ahmed A El-Husseiny  4 ,  Hesham A El-Mahdy  4 ,  Eslam B Elkaeed  5 ,  Ibrahim H Eissa  6
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.
PMID: 34923885 DOI: 10.1080/14756366.2021.2015342
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.
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