Regioisomeric polyether-linked bis-hydrazothiazoles: architecture as cancer terminators in liver carcinoma via...

Development of two regioisomeric sets of polyether-linked bis-hydrazothiazole derivatives that could be used as anticancer prototypes.

Two construction scaffolds, bis-phenacyl bromide 4 and bis-thiosemicarbazones 6a,b were utilized as efficient building blocks to access desired bis-hydrazothiazole derivatives 8a-l and 10a-l. These bis-thiazoles were screened against four different cancer cell lines - liver (HepG-2), lung (A-549), colorectal (HCT-116), and prostate (PC-3). Computational simulations of the most potent bis-hydrazothiazoles using molecular docking assessment (RMSD, 1.15 Å) were utilized to support in vitro experimental findings.

The new bis-thiazoles 8a-l and 10a-l showed varying levels of mild to good cytotoxicity, with chloro-substituted derivatives 8c, 8i, 10c, and 10i showing notable cytotoxicity and selectivity against liver carcinoma with IC₅₀: 10.3, 12.2, 23.9, and 11.1 µM, respectively. Cell cycle arrest is propelled by inducing total apoptosis from 0.18% for the untreated control cells to 18.63, 28.13, 35.68, and 16.07% for bis-thiazoles 8c, 8i, 10c, and 10i, respectively. Molecular docking showed the ability of the most potent bis-hydrazothiazoles 8c, 8i, 10c, and 10i to inhibit Pim-1 kinase.

Two novel regioisomeric sets of polyether-linked bis-hydrazothiazoles were developed. These new bis-heterocycles have been proven to be highly selective anticancer prototypes against HepG2 carcinoma.