Design,Synthesis And Bioactivity Of 1,2,4-thiadiazole Derivatives

The substituted 1,2,4-thiadiazoles have demonstrated wide spectrum of biological activity and significant applications in medicinal chemistry.In order to discover new bioactivity of substituted1,2,4-thiadiazoles,a library of small molecules compounds with structural diversity of 1,2,4-thiadiazole heterocycles were constructed in this thesis.In case of successful identification of novel small molecules with anti-bacterial or anti-cancer,then corresponding chemical probes will be synthesized for chemical-proteomic identification of cellular targets,and it would lay the foundation for developing the new medicine.A series of C-H bond functionalized reactions by 1,2,4-thiadiazole as directing group were developed.In this dissertation,we have constructed a small molecule library comprised of 1,2,4-thiadiazole heterocycles,and the initial exploration of its antibacterial and antitumor activity were screened.The results were summarized as follows:1.A novel,simple protocol is disclosed for the synthesis of thioamides starting from aryl nitriles and sodium sulfide?Na₂S·9H₂O?.In this reaction,readily available,inexpensive inorganic salt?Na₂S·9H₂O?serves as the sulfur source and various functional groups of aryl nitriles were well.In addition,this method can be applied in concise synthesis of ethionamide.Moreover,1,2,4-thiadiazoles were prepared by thioamides with Na₂-Eosin Y-sensitized titanium dioxide as catalyst through visible light irradiation and only 0.3%catalysts were used.2.Ir-catalyzed ortho-C-H sulfonication directed by 1,2,4-thiadiazole auxiliary using sulfonyl azides as the amino source,and the catalytic reaction was performed in water to synthesize 1,2,4-thiadiazoles with sulfonamides.We also present herein the[Cp*IrCl₂]₂-catalyzed addition of aromatic rings to maleimides assisted by a 1,2,4-thiadiazoles directing group.This method allows the synthesis of a wide range of synthetically meaningful succinimide derivatives.Furthermore,maleates are also suitable substrates,which convincingly demonstrates the universality of our protocol.3.Rh-catalyzed ortho-C-H cyanation directed by 1,2,4-thiadiazole using the readily available N-cyano-N-phenyl-p-toluenesulfonamide?NCTS?as the nitrile source,and the catalyst system exhibits excellent chemo-and regioselectivity to synthesize 1,2,4-thiadiazoles with nitrile.We have developed catalytic meta-selective C_Ar-H nitration of aromatics using Ru₃?CO?₁₂ as the catalyst,and Cu?NO₃?₂·3H₂O as the nitro source to synthesize 1,2,4-thiadiazoles with nitro.4.The inhibitory activity of staphylococcus aureus and escherichia coli were studied on the parent compound of 3,5-diaryl-1,2,4-thiadiazole,and showed little inhibition.However,the compounds with sulfonamides or succinimides showed the inhibitory activity,these molecules may be combined with targeted proteins by hydrogen bonding to increase their activity.Some compounds were assayed for their anti-proliferation activity toward breast cancer MCF-7 cell,and the compound N,3-diphenyl-1,2,4-thiadiazole-5-amine with succinimide had potential inhibitory effects on MCF-7 cell.In summary,through development of new synthetic methods,we have constructed a small molecule library comprised of 1,2,4-thiadiazole heterocycle.Phenotype-based screening for the discovery of new anti-cancer and anti-bacterial small molecules is ongoing in our library.