5-(Thiophen-2-yl)-1,3,4-thiadiazole derivatives: synthesis, molecular docking and in vitro cytotoxicity evaluation as potential anticancer agents

Sobhi M Gomha,1 Mastoura M Edrees,2,3 Zeinab A Muhammad,2 Ahmed AM El-Reedy4 1Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt; 2Department of Organic Chemistry, National Organization for Drug Control and Research (NODCAR), Giza, Egypt; 3Department of Chemistry, Faculty of Science, King Khalid University, Abha, Saudi Arabia; 4Department of Basic and Applied Science, Faculty of Oral and Dental Medicine, Nahda University, Beni-Suef, Egypt Background: Nowadays, cancer is an important public health problem in all countries. Limitations of current chemotherapy for neoplastic diseases such as severe adverse reactions and tumor resistance to the chemotherapeutic drugs have been led to a temptation for focusing on the discovery and development of new compounds with potential anticancer activity. The importance of thiophene and thiadiazole rings as scaffolds present in a wide range of therapeutic agents has been well reported and has driven the synthesis of a large number of novel antitumor agents. Methods: A series of new 1,3,4-thiadiazoles were synthesized by heterocyclization of N-(4-nitrophenyl)thiophene-2-carbohydrazonoyl chloride with a variety of hydrazine-carbodithioate derivatives. The mechanisms of these reactions were discussed and the structure of the new products was elucidated via spectral data and elemental analysis. All the new synthesized compounds were investigated for in vitro activities against human hepatocellular carcinoma (HepG-2) and human lung cancer (A-549) cell lines compared with cisplatin standard anticancer drug. Moreover, molecular docking using MOE 2014.09 software was also carried out for the high potent compound 20b with the binding site of dihydrofolate reductase (DHFR, PDB ID (3NU0)). Results: The results showed that compound 20b has promising activities against HepG-2 and A-549 cell lines (IC50 value of 4.37±0.7 and 8.03±0.5 μM, respectively) and the results of molecular docking supported the biological activity with total binding energy equals -1.6 E (Kcal/mol). Conclusion: Overall, we synthesized a new series of 1,3,4-thiadiazoles as potential antitumor agents against HepG-2 and A-549 cell lines. Keywords: hydrazonoyl chlorides, hydrazine-carbodithioates, 1,3,4-thiadiazoles, molecular docking, anticancer activit