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Abstract
Available treatments for leishmaniasis have been widely used since the 1940s but come at a high cost, variable efficacy, high toxicity, and adverse side-effects. 3,3′,5,5′-Tetramethoxy-biphenyl-4,4′-diol (TMBP) was synthesized through laccase-catalysis of 2,6-dimethoxyphenol and displayed antioxidant and anticancer activity, and is considered a potential drug candidate. Thus, this study aimed to evaluate the anti-leishmanial effect of TMBP against promastigote and amastigote forms of Leishmania (L.) amazonensis and investigated the mechanisms involved in parasite death. TMBP treatment inhibited the proliferation (IC50 0.62–0.86 µM) and induced the death of promastigote forms by generating reactive oxygen species and mitochondrial dysfunction. In intracellular amastigotes, TMBP reduced the percentage of infected macrophages, being 62.7 times more selective to the parasite (CC50 53.93 µM). TMBP did not hemolyze sheep erythrocytes; indicative of low cytotoxicity. Additionally, molecular docking analysis on two enzyme targets of L. amazonensis: trypanothione reductase (TR) and leishmanolysin (Gp63), suggested that the hydroxyl group could be a pharmacophoric group due to its binding affinity by hydrogen bonds with residues at the active site of both enzymes. TMBP was more selective to the Gp63 target than TR. This is the first report that TMBP is a promising compound to act as an anti-leishmanial agent.
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1 Universidade Estadual de Londrina, Departamento de Química, Centro de Ciências Exatas, Londrina, Brazil (GRID:grid.411400.0) (ISNI:0000 0001 2193 3537)
2 Instituto Carlos Chagas, Fiocruz, Programa de Pós-Graduação em Biociências e Biotecnologia, Curitiba, Brazil (GRID:grid.418068.3) (ISNI:0000 0001 0723 0931); Universidade Estadual de Londrina, Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Londrina, Brazil (GRID:grid.411400.0) (ISNI:0000 0001 2193 3537)
3 Universidade Estadual de Londrina, Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Londrina, Brazil (GRID:grid.411400.0) (ISNI:0000 0001 2193 3537)
4 Universidade Federal Do Rio de Janeiro, Instituto de Química, Rio de Janeiro, Brazil (GRID:grid.8536.8) (ISNI:0000 0001 2294 473X)
5 Universidade Tecnológica Federal do Paraná, Programa de Pós-Graduação em Engenharia Ambiental, Londrina, Brazil (GRID:grid.474682.b) (ISNI:0000 0001 0292 0044)