Synthesis,biological Evaluation And Molecular Docking Of Novel 1,3,4-thiadiazol-2-amide Derivatives As Antitubulin Agents

As the increase of environmental pollution and the increase of stress at work,one of the important disease of cancer has become a serious threat to human health.Therefore,the development of new anti-cancer drugs is very important to human survival.Due to the extreme importance of microtubules in the process of mitosis,microtubules have been recognized as one of the successful and efficacious drug targets for the development of novel anti-cancer chemotherapeutics.Microtubule-inhibiting agents(MIAs)currently have been used in clinic therapies work through the suppression of the microtubule dynamics by misdirecting the formation of a functional mitotic spindle in fast dividing tumor cells.This arrests the cells in M phase,thereby leading to apoptosis of the tumor cells.1,3,4-Thiadiazoles are five-membered ring systems that have gained prominence by exhibiting a wide variety of biological activities as well as producing useful intermediates in several organic preparations.1,3,4-Thiadiazole derivatives have been reported to be anticancer,antimicrobial,anti-tubercular,anti-inflammatory and analgesic.The action of 1,3,4-thiadiazoles connected with the apoptotic mechanisms and angiogenesis,which is a crucial step in the tumorigenesis seems to be very promising in anticancer therapy.Besides,amide derivatives were associated with broad spectrum of biological activities including antitumor properties and many tubulin binding agents containing the amide moieties are now first-line clinical drugs or currently in clinical trials for the treatment of solid tumors.Moreover,a series of 1,3,4-thiadiazol-2-amide derivatives have been well designed and found to be differentiating inducers of human cancer cells.On this basis,in order to find compounds processing better tubulin inhibitory activity,the Ligand Fit Dock protocol of Discovery Studio was used as the in silico screening tool.a series of novel compounds(6a-w)bearing thiadiazol skeleton and amide moiety has been synthesized and evaluated as tubulin polymerization inhibitors.Among all the designed compounds,compound 6f exhibited the most potent anticancer activity against A549,MCF-7 and HepG2 cancer cell lines with IC50 values of 0.03 ± 0.01μM,0.06 ± 0.03 μM and 0.05 ± 001μM,respectively.Compound 6f also exhibited significant tubulin polymerization inhibitory activity(IC50=1.73±0.28 μM,which was superior to the positive control.Furthermore,we also showed that 6f was a potent inducer of apoptosis in A549 cells and it had cellular effects typical for microtubule interacting agents,causing accumulation of cells in the G2/M phase of the cell cycle.In order to further investigate the mode of action between them,we performed molecular simulation.The result.showed that compound 6f was nicely bound to the tubulin via two hydrogen bonds and a π-cation bond,which might give the support to these results.