Synthesis And In Vitro Antiproliferative Evaluation Of Novel Nonsymmetrical 1,3,4-thiadiazole Disulfide Derivatives Bearing Anilino Moiety

Cancer is a major global health problem,due to metastasis,proliferation and differentiation of tumor cell uncontrollable,it has become the second leading cause of death after cardiovascular disease etiology.At present,many anticancer drugs have high toxicity and drug resistance problems.Therefore,there is an urgent need to develop new anticancer drugs.1,3,4-thiadiazole is a five-member ring containing nitrogen and sulfur two heteroatoms,with many types of biological activities,such as antioxidant,antibacterial,antifungal,anticancer,anti-inflammatory,antiepileptic,insecticide and weeding.As an important sulfur-containing compound,disulfide derivatives displayed many types of biological activities,such as anticancer,antibacterial,antifungal and anti-inflammatory.Among them,antitumor activity has become the focus of dithioether derivatives.Considering the biological significance of 1,3,4-thiadiazole and disulfide derivatives,we report herein the synthesis of nonsymmetrical 1,3,4-thiadiazole disulfide derivatives bearing anilino moiety.All newly synthesized compounds were characterized by IR,1H NMR,13 C NMR and High Resolution-Electrospray Ionization-Mass Spectrometer(HR-ESI-MS).1-methylpropyl 2-imidazolyl disulfide(PX-12)and 5-fluorouracil(5-FU)were used as positive controls,we evaluated for their in vitro antiproliferative activities against human cancer cell lines SMMC-7721,A549,Hela and normal cell line L929 by CCK-8 assay.The bioassay results demonstrated that some compound showed higher activities than positive control PX-12 and 5-FU in SMMC-7721 cell line,among them,compounds 9v、9x、9w and 9s showed efficient antiproliferative activities,with IC50 value of 2.86、3.21、3.22 and 3.59 μM;in A549 cell line,the majority of them showed better activities than positive control PX-12 and 5-FU,especially compound 9x exhibited the best inhibitory effect with IC50 value of 4.29 μM;in Hela cell line,most of compounds showed better activities than positive control PX-12 and 5-FU,among these compounds,compound 9q、9x、9w and 9v showed significant antiproliferative activity with IC50 value of 3.59、4.41、5.14 and 5.42 μM;in L929 cell line,most of compounds showed weak cytotoxic effect.In summary,24 target compounds exhibited antiproliferation with different degrees against SMMC-7721,A549 and Hela,and most of compounds showed weak cytotoxic effect against the normal cell line L929.Therefore,the results laid a foundation for the structure-function relationship and action mechanism research of this series of compounds.