Structure-Based Design, Synthesis, and Biological Evaluation of Oxadiazole-Morpholine Hybrids as Potent PARP-1 Inhibitors Inducing Apoptosis in Breast Cancer Cells.

Poly(ADP-ribose) polymerase-1 (PARP-1) plays a central role in the repair of DNA single-strand breaks and represents an established therapeutic target in cancer treatment. In this study, a series of novel oxadiazole-morpholine hybrid compounds was designed and synthesized using a structure-based drug design approach to target the catalytic domain of PARP-1. The synthesized compounds were evaluated for their cytotoxic activity against breast and ovarian cancer cells, PARP-1 inhibitory potency, and apoptosis-inducing effects. Among the tested compounds, 12a exhibited potent cytotoxic activity against MDA-MB-231 cells (IC50 = 1.23 μM), surpassing the reference drug olaparib (IC50 = 3.45 μM). Compound 12a also demonstrated strong PARP-1 inhibitory activity (IC50 = 0.034 μM), comparable to olaparib (IC50 = 0.012 μM). Flow cytometric analyses revealed that compound 12a significantly induced apoptotic cell death and altered cell cycle progression. Molecular docking studies suggested plausible binding interactions within the PARP-1 catalytic site, supporting the observed biological activity. These findings identify oxadiazole-morpholine hybrids as promising scaffolds for further optimization as PARP-1 inhibitors.