Synthesis And Biological Evaluation Of New2-(Benzylthio)-5-aryloxadiazole Derivatives

Epidermal growth factor receptor (EGFR) plays a critical role in regulating cell proliferation, differentiation, and migration. The up-regulated activity of EGFR correlates with many human tumors, including lung, breast, bladder, prostate, and kidney cancers. It has been also observed the overexpression of EGFR in breast cancer, ovarian cancer and so on. Therefore, EGFR tyrosine kinase represents an attractive target for the development of novel anti-cancer agents. As this kind of inhibitors, gefitinib and erlotinib have been approved by US FDA for treatment of patients with non small-cell-lung cancer (NSCLC).Oxadiazole ring as a building element can be seen in many natural products. Compounds containing one or more oxadiazole ring have various activities such as hypoglycemic, anti-fungal, anti-inflammatory, anti-bacterial and anti-tumor activities. The previous literatures few involve in the anti-tumor drug target for this oxadiazole derivatives when they describe their anti-tumor activities.For further study of the interaction with the probable target of this derivatives and to obtain leading compounds with better bioactivities, we design and synthesize twenty2-(benzylthio)-5-aryl-1,3,4-oxadiazole derivatives. Thirteen compounds are completely new compounds. The result of anti-proliferative in vitro indicates that this5-aryloxadiazole derivatives display more potent anti-proliferative activity in MCF-7cell line than the other two tumor cell lines. In particular, 2-(5-(benzylthio)-1,3,4-oxadiazol-2-yl)aniline, compound3e displays the most potent anti-proliferative activity with IC50of1.09μM, superior to the positive control gefitinib. Further EGFR inhibitory activity experiment can demonstrate that this5-aryloxadiazole derivatives could play their role by inhibiting EGFR.In addition, the result of molecular docking also shows that compound3e could bind to ATP binding site of EGFR kinase. The hydrogen bond and Pi-Pi interaction stabilize the enzyme-ligand complex, which are formed with MET769and LYS721, respectively. The formation mode of hydrogen bond as well as the trend of compound’s conformation in ATP binding site is similar to the known EGFR inhibitor Erlotinib. This finding further demonstrates this5-aryloxadiazole derivatives can be able to perform their antiproliferation via inhibiting the function of EGFR. As a result, it explains a possible mode of this derivatives interacting with EGFR from molecular aspect.