| Summary: | Leishmaniasis is a neglected tropical disease caused by <i>Leishmania</i> species. Available therapeutic options have several limitations. The drive to develop new, more potent, and selective antileishmanial agents is thus a major goal. Herein we report the synthesis and the biological activity evaluation against promastigote and amastigote forms of <i>Leishmania amazonensis</i> of nine 4,8-dimethoxynaphthalenyl chalcones. Compound ((E)-1-(4,8-dimethoxynaphthalen-1-yl)-3-(4-nitrophenyl)prop-2-en-1-one), <b>4f</b>, was the most promising with an IC<sub>50</sub> = 3.3 ± 0.34 μM (promastigotes), a low cytotoxicity profile (CC<sub>50</sub> = 372.9 ± 0.04 μM), and a high selectivity index (SI = 112.6). Furthermore, <b>4f</b> induced several morphological and ultrastructural changes in the free promastigote forms, loss of plasma membrane integrity, and increased reactive oxygen species (ROS). An in silico analysis of drug-likeness and ADME parameters suggested high oral bioavailability and intestinal absorption. Compound <b>4f</b> reduced the number of infected macrophages and the number of amastigotes per macrophage, with an IC<sub>50</sub> value of 18.5 ± 1.19 μM. Molecular docking studies with targets, ARG and TR, showed that compound 4f had more hydrogen bond interactions with the ARG enzyme, indicating a more stable protein-ligand binding. These results suggest that 4,8-dimethoxynaphthalenyl chalcones are worthy of further study as potential antileishmanial drugs.
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