Synthesis and evaluation of new benzoxazole derivatives as potential antiglioma agents

Abstract

Gliomas account for the majority of human brain tumors and the incidence of gliomas is expected to rise in upcoming years and therefore extensive efforts have been devoted to the discovery of potent antiglioma agents. Due to the importance of benzoxazoles for anticancer drug discovery, herein new benzoxazole-based hydrazone derivatives (3a-g) were designed and synthesized. The cytotoxic effects of the compounds on C6 rat glioma and NIH/3T3 mouse embryonic fibroblast cell lines were investigated using MTT assay. The apoptotic effects of the most selective anticancer agent were analyzed based on Annexin V-PI binding capacities in flow cytometry. The compounds were also investigated for their acetylcholinesterase (AChE) inhibitory effects using a modification of Ellman’s spectrophotometric method. In order to evaluate the compliance of the compounds to Lipinski’s rule of five, their physicochemical parameters were determined using Molinspiration software. N'-([1,1'-Biphenyl]-4-ylmethylene)-2-[(5- fluorobenzoxazol-2-yl)thio]acetohydrazide (3g) was found to be more effective on C6 cell line (IC50= 4.30±0.28 µg/mL) than mitoxantrone (IC50= 4.56±1.24 µg/mL). The high SI value of compound 3g indicated that its antiglioma activity was selective. This compound caused late apoptosis in a dose dependent manner. Compound 3g was also found to be the most effective AChE inhibitor in this series. According to in silico studies, compound 3g only violated one parameter of Lipinski’s rule of five. On the basis of Lipinski’s rule, the compound was expected to have reasonable oral bioavailability. According to in vitro and in silico studies, compound 3g stands out as a promising antiglioma agent for further studies.

Keywords

• Acetylcholinesterase
• apoptosis
• benzoxazole
• glioma
• hydrazone

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