Synthesis, Biological Evaluation And Molecular Docking Studies Of 1,3,4-oxadiazole Derivatives As Potential Antitumor Agents

The identification and development of novel compounds for the cancer therapy is an important task in pharmaceutical research. In order to kill the tumor cells more effectively and overcome the side effects of chemotherapy drugs, the research and development of the targeted drugs become the focus of anti-tumor drugs.Focal adhesion kinase (FAK) was identified as a highly tyrosine-phosphorylated protein it is activated and tyrosine phosphorylated in response to integrin clustering, which result in signal transmission to the cell nucleus to trigger cell division and motility. FAK plays an important role in cell proliferation, survival, motility, invasion, metastasis, and angiogenesis. FAK was found at elevated levels in most human cancers, particularly when cancer transformed into highly invasive metastases. Thus FAK has become a potential target for the design and development of anti-tumor agents.Azoles derivatives possess a variety of bioactivity. Remarkably, a few differently substituted 1,3,4-oxadiazoles, triazoles have been found to exhibit anti-cancer activities which establishes this moiety as a member of the privileged structures class in pharmaceutical fields. Primary research showed that compounds containing 1,3,4-oxadiazoles possessed a variety of biological activities, such as antitumor, anti-inflammatory, hypoglycemic, antifungal and antibacterial activities. In addition, Usman Ghani reported some 1,3,4-oxadiazoles derivatives as the potent inhibitors of tyrosinase.In this procedure, the Ligand Fit Dock protocol of Discovery Studio 3.1 was used as thein silico screening tool. The compounds which revealed the highest binding affinities were owned lowest predicted binding free energies. After screening from our compound collection, on the basis of their binding affinities with the ATP-binding pocket of FAK, one initially hits were selected for protein kinase inhibitory activity screening. Then 17 benzotrizole derivatives (5a-5q) with oxadiazole skeleton were synthesized and evaluated as FAK inhibitors.The synthesis of these derivatives was started from benzene-1,2-diamine on the treatment with CH3COOH and NaNO2 solution to give compound 2. Compound 2 was N-esterified with ethyl chloroacetate in methanol to give ethyl 1,2,3-benzo[d]triazol-l-ylacetate 3, which was on hydrazination with hydrazine hydrate afforded 1,2,3-benzo[d]triazol-1-ylacetic hydrazide 4. Compound 4 carried on treatment with different aromatic carboxylic acids in the presence of phosphoryl chloride yielded the compound 5. All of the synthetic compounds were given satisfactory analytical and spectroscopic data, which were in full accordance with their depicted structure.The synthesized oxadiazole derivatives 5a-5q were evaluated for their antitumor activities against HeLa (human cervical carcinoma cell line), HepG2 (human hepatoma cell line) and MCF-7 (human breast cancer cell line) cells. Compound 5h displayed the most potent antitumor activity with an IC50 of 10.77 nM against HeLa cells,15.49nM against HepG2 cells and 334.2nM against MCF-7 cells. And the small-molecule docking simulations were performed to give the probable binding modes of these compounds into the active binding site of FAK, which would give the support to these results. Compound 5h was stabilized by hydrogen bonding interaction between methoxy group with ARG426 and a π-cation interaction between oxadiazole ring with ILE428.Targeted drugs has shown more advantages in clinical treatment than chemotherapy drugs, it must be the hot spot of anticancer drug research and development.