Synthesis And Biological Evaluation Of Novel 1,3,4-oxadiazole Derivatives Possessing Benzotriazole Moiety

1,3,4-oxadiazole derivatives have drawn much attention as the lead compounds with a variety of biological activity. Many different substituent 1,3,4- oxadiazole derivatives have been proved a good wider spectrum of activity—anti-tumor, anti-microbial, anti-inflammatory, anti-convulsion, antioxidant. Meanwhile, plenty of references reported that compounds possessing benzotriazole moiety showed remarkable result in anti-inflammatory, antirheumatic, anti-proliferative, antituberculous, anti-tumor and so on.Focal Adhesion Kinase (FAK), which is a kind of tyrosine protein kinase, occupies an important position in cell signaling transduction. FAK is the centre that cell signaling goes inside and outside, mediating multiple signaling pathways. According to research, FAK plays an important role in the process that tumor to be malignant and FAK affects cell growth, metabolism, proliferation through a series of downstream signal after activation. Therefore, inhibiting FAK may have potential antitumor efficacy.With the aid of computer aided drug design (CADD), we designed and synthesized nineteen 1,3,4-oxadiazole derivatives containing benzotriazole moiety. Screening benzotriazole as the starting material, after esterification, hydrazide, CS2 cyclization, and reacting with different substituent benzyl bromide, we gained the final compounds 4-22. By 1H NMR and MS means, we confirmed the structure of the compounds 4-22. Also, we did biological activity research and made FAK as drug target. All of those compounds were reported for the first time.All the nineteen synthesized 1,3,4-oxadiazole derivatives were evaluated for their anti-proliferative activity against two human cancer cells, MCF-7(human breast cancer cell) and HT29(human colon cancer cell). The results indicated that most of the compounds had good anti-tumor activity and better inhibition effect against MCF-7. Among the compounds, compound 4 show the most potent inhibitory activity against MCF-7 and HT29 cell lines with IC50 values of 5.68 μg/mL and 10.21 μg/mL, which compared to positive control. Besides, all the compounds were assayed for FAK inhibitory activity. The results showed compound 4 exhibited the most potent FAK inhibitory activity with IC50 values of 1.2±0.3 μM. The small-molecule docking simulations were performed to give the probable binding modes of these compounds into the active binding site of FAK. The binding energy △G of compounds 4-22 docking with FAK was all negative, illustrating that the docking was easy. Taking compound 4 as an example, which owned the maximal absolute value, we could see the interaction in detail through 2D and 3D figure of the docking result. Based on the above research, the nineteen 1,3,4-oxadiazole derivatives containing benzotriazole moiety may have good research prospect as FAK inhibitor.