Biology, Vol. 14, Pages 1709: From Dyes to Drugs? Selective Leishmanicidal Efficacy of Repositioned Methylene Blue and Its Derivatives in In Vitro Evaluation

Biology doi: 10.3390/biology14121709

Authors:
Deyvison Rhuan Vasco-dos-Santos
Juliana Almeida-Silva
Ludmila Ferreira de Almeida Fiuza
Natalia Vacani-Martins
Zênis Novais da Rocha
Maria de Nazaré Correia Soeiro
Andrea Henriques-Pons
Eduardo Caio Torres-Santos
Marcos André Vannier-Santos

Chemotherapy for cutaneous leishmaniasis is hindered by high toxicity, adverse effects, and increasing drug resistance. Thus, safer and more selective therapies are urgently required. Here, we evaluated the antiparasitic efficacy of methylene blue (MB) and new MB, as well as novel ruthenium complex derivatives (NMB-B and NMB-P) against promastigote and amastigote forms of Leishmania amazonensis. Their cytotoxicity and selectivity on L929, HepG2, VERO, J774.G8 cells, and murine peritoneal macrophages were measured. Mechanisms of action were explored via flow cytometry, assessing morphological changes, mitochondrial depolarization, ROS production, and cell death. The compounds inhibited parasite proliferation in a dose and time-dependent manner, achieving submicromolar efficacy against amastigotes (NMB-P = 0.46 μM). No cytotoxicity was observed on L929, J774.G8, and VERO cells (except NMB), while HepG2 and murine peritoneal macrophages showed low to moderate toxicity. Selective indexes reached 84 for promastigotes and over 500 for amastigotes. The compounds induced mitochondrial depolarization by up to 61% and a five-fold increase in ROS levels, leading to structural damage and parasite death via late apoptosis/necrosis-like mechanisms. These findings indicate that the compounds act selectively and trigger the release of oxidative species, exerting leishmanicidal activity and warranting further investigation.

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Deyvison Rhuan Vasco-dos-Santos www.mdpi.com