Development of an Environment-Friendly and Electrochemical Method for the Synthesis of an Oxadiazole Drug-Scaffold That Targets Poly(ADP-Ribose)Polymerase in Human Breast Cancer Cells

Abstract

The development of environment-friendly new Poly-adenosine diphosphate (ADP)-ribose Polymerase (PARP) inhibitors are highly essential because of their involvement in the survival of cancer cells. Therefore, a library of indazolyl-substituted-1,3,4-oxadiazoles known to inhibit PARP in cancer cells was synthesized by a green protocol. Furthermore, the cytotoxic effects of these compounds were evaluated in human MCF-7 breast cancer (BC) cells, which revealed that the compound 2-(3-bromo-4-nitrophenyl)-5-(1-methyl-1H-indazol-3-yl)-1,3,4-oxadiazole (8) inhibited viability with an IC50 value of 1.57 µM. Since the oxadiazole structure was extensively used in medicinal chemistry applications, the reported environment-friendly protocol was superior to the conventional method. Further, computational mechanistic studies revealed that the oxadiazole ring formation occurred spontaneously when compared to the conventional method. Additionally, the in silico bioinformatic studies of oxadiazole binding towards PARP1 showed that compound 8 could bind to PARP1 with higher binding energy (BE) of −7.29 kcal/mol when compound to compound 5s (BE = −7.17 kcal/mol), a known PARP cleavage oxadiazole structure (2-(3,4-Dimethoxybenzyl)-5-(3-(2-fluoro-3-methylpyridin-4-yl)phenyl)-1,3,4-oxadiazole) indicative of the improvement in the optimization process. In conclusion, a newer indazolyl-oxadiazole compound is reported, which could serve as a lead in developing PARP inhibitors in BC cells.

Keywords

• 1,3,4-oxadiazoles
• poly(ADP-ribose) polymerase
• human breast cancer
• auto dock
• density function theory