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. 2022 Dec;37(1):380-396.
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

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

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

Mohamed Hagras et al. J Enzyme Inhib Med Chem. 2022 Dec.

Erratum in

  • Correction.
    [No authors listed] [No authors listed] J Enzyme Inhib Med Chem. 2022 Dec;37(1):514. doi: 10.1080/14756366.2022.2024999. J Enzyme Inhib Med Chem. 2022. PMID: 34986713 Free PMC article. No abstract available.

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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Conflict of interest statement

No potential conflict of interest was reported by the authors.

Figures

Figure 1.
Figure 1.
Some reported VEGFR-2 inhibitors (I, II, III, and IV) and the target compounds (5–18) having the same pharmacophoric features.
Scheme 1.
Scheme 1.
Synthesis of the target compounds 5–18. Reagents and conditions: (a) C2H5OH/H2SO4; (b) NH2NH2·H2O/C2H5OH; (c) CS2\KOH, EtOH; (d) RX/EtOH, NaOAc.
Figure 2.
Figure 2.
The inhibitory effects of the compounds tested on VEGFR-2 in HepG2 cells compared to sorafenib. The data are presented as the mean ± SEM of three different experiments. *Significant from control group at p < 0.001 using unpaired t-test.
Figure 3.
Figure 3.
Flow cytometric analysis of cell cycle phases after compound 5 treatment of HepG2 cells. (A) The representative histogram depicts the cell cycle distribution of control (HepG2) cells; (B) the representative histogram depicts the cell cycle distribution of compound 5-treated cells. (C) A column graph depicts the percentage of cells in each phase of the cell cycle in both control (HepG2) and compound 5 treated cells. The percentages are given as the mean SEM of three different experiments. Using unpaired t-tests, *p < 0.05 indicates statistically significant differences from the untreated control (HepG2) group.
Figure 4.
Figure 4.
In HepG2 cells, compound 5 caused apoptosis. (A) Control, (B) Compound 5, and (C) represent the graphical representation of the percent of apoptotic and necrotic cells in control (HepG2) cells and compound 5 treated cells. The percentages are given as the mean SEM of three different experiments. Using unpaired t-tests, *p < 0.05 indicates statistically significant differences from the untreated control (HepG2) group.
Figure 5.
Figure 5.
Effects of compound 5 on Caspase 3 level in HepG2 cells. Values are reported as mean ± SEM of three different experiments. *p < 0.001 indicates statistically significant differences from the untreated control (HepG2) group using unpaired t-test.
Figure 6.
Figure 6.
Interaction of sorafenib with VEGFR-2.
Figure 7.
Figure 7.
Interaction of compound 5 with VEGFR-2.
Figure 8.
Figure 8.
Interaction of compound 8 with VEGFR-2.
Figure 9.
Figure 9.
Interaction of compound 17 with VEGFR-2.
Figure 10.
Figure 10.
Predicted binding mode of compound 18 with the active site of VEGFR-2.
Figure 11.
Figure 11.
The expected ADMET studies.
See this image and copyright information in PMC

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