Exploration of mercaptoacetamide-linked pyrimidine-1,3,4-oxadiazole derivatives as DNA intercalative topo II inhibitors: Cytotoxicity and apoptosis induction

The design and synthesis of a new series of mercaptoacetamide-linked pyrimidine-1,3,4-oxadiazole hybrids was accomplished. The in vitro cytotoxic potential of these new compounds was evaluated against lung cancer (A549), prostate cancer (PC-3, DU-145) and human embryonic kidney (HEK) cell lines. Compound 9p showed the highest potency on A549 cells with an IC50 value of 3.8 +/- 0.02 mu M. Moreover, 9p was found to be 25-fold more selective towards cancer cell lines than the non-cancerous (HEK) cell line. The target-based assay revealed the inhibition of the topoisomerase II enzyme by compound 9p. UV-visible spectroscopy, fluorescence, circular dichroism (CD), and viscosity studies inferred the intercalative property and effective binding of compound 9p with CT-DNA. Apoptosis induced by the compound 9p was observed by various morphological staining assays, i. e, DAPI, EtBr/AO. Further, the molecular modeling studies revealed the binding of compound 9p at the active site of the DNA-topoisomerase II complex while the physicochemical properties were in the recommended range. Finally, mercaptoacetamide-linked pyrimidine-1,3,4-oxadiazole derivatives can be considered as a promising scaffold for development as effective anticancer agents and topoisomerase II inhibitors.

Automated summary

A new series of mercaptoacetamide-linked pyrimidine-1,3,4-oxadiazole hybrids were designed and synthesized. The in vitro cytotoxic potential of these compounds was evaluated against various cancer cell lines, and compound 9p showed high potency and selectivity. The compound was found to inhibit the topoisomerase II enzyme and bind effectively with CT-DNA, leading to apoptosis. Molecular modeling studies confirmed the binding of compound 9p at the active site of the DNA-topoisomerase II complex. These findings suggest that mercaptoacetamide-linked pyrimidine-1,3,4-oxadiazole derivatives could be promising scaffold for the development of effective anticancer agents and topoisomerase II inhibitors.