1,3,4-Thiadiazoline−coumarin hybrid compounds containing D-glucose/D-galactose moieties: Synthesis and evaluation of their antiproliferative activity

Abstract

We synthesized a new series of 1,3,4-thiadiazoline−coumarin hybrid compounds that contain d-glucose and d-galactose moieties (9a-g) and evaluated their cytotoxic activity against breast adenocarcinoma (MCF-7), human liver cancer (HepG2), human cervical cancer (HeLa), human melanoma cancer (SK-Mel-2), and human lung cancer (LU-1) cells. To reveal their selectivity toward cancer cells, the compounds were also tested against human fibroblast cell line, MRC-5. Synthesized compounds exhibited potent cytotoxic activity against the tested cell lines with IC50 values of 1.18–11.81, 1.72–9.43, 1.98–13.16, 1.82–11.25, and 2.25–14.62 μM (against MCF-7, HepG2, HeLa, SK-Mel-2, and LU-1 cells, respectively) compared to Sorafenib, 5-FU, and DOX. The long and branched-terminal carbon chains often increased activity. Interestingly, compounds 9a-g displayed selectivity toward cancer cell lines over MRC-5 (IC50 3.93–25.55 μM). These compounds also displayed potent inhibitory activity against EGFR and HER2 kinases (IC50 0.22–0.47 and 0.13–0.35 μM, respectively) compared to the standard drug, Sorafenib (IC50 = 0.11 and 0.13 μM, respectively). Molecular docking study also employed to identify the structural features required for the EGFR/HER2 inhibitory activity of the new series.

Keywords

• 4-Formylcoumarins
• 1,3,4-Thiadiazolines
• EGFR
• HER2
• Antiproliferative
• Molecular docking