Synthesis, Biological Evaluation And Molecular Docking Studies Of Novel1,3,4-Thiadiazole Derivatives As Potential Focal Adhesion Kinase (FAK) Inhibitors

Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung, which is the leading cause of cancer-related death. A variety of reasons can cause lung cancer, the most common cause is long-term exposure to tobacco smoke, which causes about85%of lung cancers. Other cases are often attributed to a combination of genetic factors, air pollution and so on. Approximately46%of lung cancer cases have metastasized when the patients are diagnosed. The traditional therapies in metastatic cancers couldn’t do so much, and the efforts focused on metastatic cancer cells to find new therapeutic strategies to cure various types of cancer, including lung cancer, are urgent needed.With the continuous development of molecular biology, new targets against cancer were exhumed by in-depth studying, and focal adhesion kinase(FAK) was one of them. It was a widely expressed non-receptor protein tyrosine kinase (PTK) and named for locating in the adhesion sites-focal adhesion. FAK played a major role in mediating signal transduction by integrins, as well as growth factor receptors. Numerous studies indicated that activated FAK mediated several signaling pathways which were involved in tumor cells’adhesion, migration and incursion. These features showed that FAK may play a key role in promoting tumorigenesis and metastasis, which made FAK one of the ideal targets for anti-cancer therapy, including advanced lung cancer.1,3,4-thiadiazoles had been used as "privileged" heterocyclic to produce substances of interest in numerous therapeutic areas. Earlier studies showed that1,3,4-thiadiazol-membered compounds having a variety of biological activity, such as anticancer, antibacterial, antiviral, etc. Variety compounds containing1,3,4-thiadiazole ring had been confirmed to have excellent antitumor activity.Gallic acid (3,4,5-trihydroxybenzoic acid; GA) was a poly-hydroxyl phenolic compound, and its derivatives had a wide range of biological activity. Among them, the mechanism of anti-cancer activity had been well investigated. The basic approach was that significantly induced the generation of reactive oxygen species (ROS), and activated the ROS-mediated apoptosis signaling pathways.Herein, in order to find compounds processing better FAK inhibitory activity, we designed and synthesized a series of new3,4,5-trimethoxybenzamide-containing1,3,4-thiadiazol derivatives by means of computer-aided drug design (CADD), and were expecting that thiadiazole and gallic acid containing enabled the object compounds to have a good activity against tumor. Then we tested antiproliferation activity against two human cancer cells, A549and MCF-7, their FAK inhibitory activity were also evaluated as well. The bioassays demonstrated that most of the synthesized compounds were proved to be potent anti-neoplastic drugs and FAK inhibitory. Among them, compound61displayed the most potent inhibitory activity, which inhibited the growth of A549and MCF-7with IC50values of0.72±0.04μM and1.32±0.08μM, while the positive control Staurosporine got IC50values of1.18±0.14μM and2.07±0.13μM. Compound61also exhibited significant FAK inhibitory activity (IC50=7.34±0.63μM). These results suggested that the anti-cancer activity of the objected compounds may be achieved by inhibiting the activity of FAK. Compound61may be useful as a lead compound for superior FAK inhibitors.