Amebicidal Effect of Adamantane–Azole Gold(I) Complexes: Cell Death Mechanisms and Synergistic Action with Chlorhexidine against <i>Acanthamoeba castellanii</i>

<i>Acanthamoeba</i> spp. are free-living protozoa associated with severe infections such as amebic keratitis and granulomatous amebic encephalitis. The absence of effective treatments highlights the need for new bioactive molecules targeting both trophozoite and cyst forms. This study evaluated the anti-<i>Acanthamoeba</i> activity of adamantane-azole gold-(I) complexes (C1 and C4) and their interaction with thioredoxin reductase (TrxR). Complexes C2, C3, and C4 exhibited potent amoebicidal activity with IC₅₀ values of 0.12, 14, and 6.2 μM, respectively. They disrupted the cell cycle and induced phosphatidylserine exposure, while C4 also triggered mitochondrial depolarization. Ultrastructural alterations, synergy with chlorhexidine, and absence of toxicity in vitro and in vivo models were observed. Molecular docking confirmed TrxR as a potential target. These findings demonstrate the therapeutic promise of C2, C3, and C4 gold-(I) complexes against <i>Acanthamoeba</i> spp. infections, combining potent activity with minimal toxicity and supporting further investigation of their mechanisms of action.