New 1,3,4-thiadiazoles derivatives: synthesis, antiproliferative activity, molecular docking and molecular dynamics

Aim: A series of 1,3,4-thiadiazole himachalene hybrids were prepared from the treatment of a himachalen-4-one thiosemicarbazone derivative with N-aryl-C-ethoxycarbonyl-nitrilimines and diarylnitrilimines via a 1,3-dipolar cycloaddition reaction. Materials & methods: The structures were confirmed by NMR, IR and high-resolution mass spectroscopy (HRMS). Results & conclusion: The newly synthesized hybrid compounds were tested for their in vitro antitumor activities against a panel of cancer cell lines including fibrosarcoma (HT-1080), lung carcinoma (A-549) and breast carcinoma (MCF-7 and MDA-MB-231). Among the tested products, 4a showed excellent activity against the HT-1080 and MCF-7 cell lines with IC50 values of 11.18 +/- 0.69 and 12.38 +/- 0.63 mu m, comparable to that of the reference drug. Docking results confirmed that the active inhibitors were well accumulated in the mushroom tyrosinase active site. Flow cytometry analysis indicated that hybrid 4a induced apoptosis and cell cycle arrest in the G(0)/G(1) phase. Molecular modeling studies affirmed the intercalative binding of compound 4a in the active site.

Automated summary

The newly synthesized hybrid compound 4a exhibited excellent anti-tumor activity against HT-1080 and MCF-7 cell lines, comparable to the reference drug. Flow cytometry analysis and molecular modeling studies confirmed the mechanism of compound 4a.