Silver(I) Ions Bridging Oxadiazole-2-thione Derivatives with Mitochondriotropic Agents: A Promising Strategy for Potent Anticancer Chemotherapy

The conjugation of phenyl-substituted 1,3,4-oxadiazole-2-thione derivatives (X-PODTH, where X = H (PODTH) (<b>1a</b>), o-F (o-F-PODTH) (<b>2a</b>), p-F (p-F-PODTH) (<b>3a</b>), o-Cl (o-Cl-PODTH) (<b>4a</b>), and m-Cl (m-Cl-PODTH) (<b>5a</b>)) with triphenylphosphine (TPP) via silver(I) ions results in the formation of heteroleptic compounds [Ag(TPP)₃(X-PODTH)] (X = H (<b>1</b>), o-F (<b>2</b>), p-F (<b>3</b>), o-Cl (<b>4</b>), and m-Cl (<b>5</b>)). These conjugates were thoroughly characterized using various techniques, including melting point (mp), X-ray fluorescence (XRF), attenuated total reflection Fourier-transform infrared (ATR-FTIR), ultraviolet-visible (UV-vis), and nuclear magnetic resonance (¹H, ³¹P NMR) spectroscopies. The crystal structures of <b>1a</b>-<b>5a</b>, and their complexes (<b>1</b>-<b>5</b>) were determined through single-crystal X-ray diffraction (XRD) and powder X-ray diffraction (PXRD) analyses. Compounds <b>1</b>-<b>5</b> demonstrated significant inhibition of human breast adenocarcinoma cell proliferation in both hormone-dependent (HD, MCF-7) and hormone-independent (HI, MDA-MB-231) cell lines. Their nongenotoxicity was confirmed <i>in vitro</i> using the micronucleus (MN) assay. The mechanism of action was further explored through studies of cell morphology, acridine orange ethidium bromide (AO/EB) staining, cell cycle arrest analysis, mitochondrial membrane permeabilization (MMP) assays, DNA binding affinity studies, and lipoxygenase (LOX) inhibitory activity. These findings were supported and rationalized through regression analysis, providing valuable insights into their structural biological activity.