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

Abstract

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.