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

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.

Synthesis of N‐(2‐(tert‐Butylamino)‐2‐oxoethyl)‐2,2‐dichloro‐N‐aryl(alkyl)acetamides as Anticancer Agents: Molecular Modeling and Biological Evaluations

“…During apoptosis, phosphatidylserine translocates to the outer plasma membrane; then Annexin V can especially detect it. Live and dead cells are identified by 7‐AAD, a DNA specific dye [18] . As shown in Figure 1, analysis of the apoptotic effect of the compound A 5 in Q1 shows necrotic cells; in Q2, cells undergoing progressive apoptosis and secondary necrosis; in Q3, cells undergoing primary apoptosis; in Q4, live cells.…”

“…Live and dead cells are identified by 7-AAD, a DNA specific dye. [18] As shown in Figure 1, analysis of the apoptotic effect of the compound A 5 in Q1 shows necrotic cells; in Q2, cells undergoing progressive apoptosis and secondary necrosis; in Q3, cells undergoing primary apoptosis; in Q4, live cells. Accordingly, after 24 hours of treatment with A 5 , our results showed that the percentages of apoptotic cells (Q2 + Q3) for 25 μM was 4.30 %; and for 50 μM, 5.67 %.…”

Design, synthesis, in silico studies, and biological evaluation of novel pyrimidine-5-carbonitrile derivatives as potential anti-proliferative agents, VEGFR-2 inhibitors and apoptotic inducers

“…These results were found to be identical to the reported data. 36 The docking score for compound 9d was −8.85 kcal mol −1 . Through its pharmacophoric group, it formed two hydrogen bonds with Glu883 and Asp1044.…”

An Understanding of Mechanism-Based Approaches for 1,3,4-Oxadiazole Scaffolds as Cytotoxic Agents and Enzyme Inhibitors

“…A good antiproliferative effect was observed for Compound ( 142 ) against both cell lines and inhibitory activity was demonstrated against VEGFR-2. It also induced 22.86% apoptosis compared to 0.51% apoptosis in control (HepG2) cells [ 129 ].…”