In Vitro Assessment of the Combined Activity of Amphotericin B and Cu2+-1,10-Phenanthroline-5,6-dione Coordination Compound Against Leishmania amazonensis Promastigotes

Leishmaniasis is a severe parasitic disease transmitted by sandflies that affects both humans and animals, with clinical manifestations ranging from cutaneous lesions to life-threatening visceral involvement. Current treatments are limited by toxicity, high cost, and the emergence of drug-resistant strains, underscoring the need for safer and more effective therapeutic strategies. In this study, we investigated the antiparasitic potential of combining Amphotericin B, a drug commonly used for leishmaniasis treatment, with 1,10-phenanthroline-5,6-dione (phendione) coordinated to copper (Cu²⁺-phendione), an experimental coordination compound, against <i>Leishmania amazonensis</i> promastigotes. The combination markedly impaired parasite proliferation, disrupted ultrastructural integrity, and interfered with metabolic activity. Mechanistic analyses revealed the presence of autophagosomes and pronounced mitochondrial alterations in treated parasites, suggesting the induction of cellular stress and the disruption of essential survival pathways. In addition, the treatment reduced the association index with THP-1 cells, indicating a decrease in parasite infectivity. Collectively, these findings demonstrate that the combination of Cu²⁺-phendione and Amphotericin B exerts potent antiparasitic effects through multiple mechanisms. Our results also showed that Cu²⁺-phendione combined with AmB displayed an additive effect, although the isobologram suggested that certain ratios approached synergy. The results support the potential of this combination as a novel chemotherapeutic approach against leishmaniasis and provide a basis for future in vivo studies to evaluate safety, efficacy, and optimal dosing strategies.