Antileishmanial Activity of 4,8-Dimethoxynaphthalenyl Chalcones on ILeishmania amazonensis/I

Leishmaniasis is a neglected tropical disease caused by Leishmania 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...

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Veröffentlicht in:Antibiotics (Basel) 2022-10, Vol.11 (10)
Hauptverfasser: de Santiago-Silva, Kaio Maciel, Bortoleti, Bruna Taciane da Silva, Oliveira, Laudicéa do Nascimento, Maia, Fernanda Lima de Azevedo, Castro, Joyce Cristina, Costa, Ivete Conchon, Lazarin, Danielle Bidóia, Wardell, James L, Wardell, Solange M. S. V, Albuquerque, Magaly Girão, Lima, Camilo Henrique da Silva, Pavanelli, Wander Rogério, Bispo, Marcelle de Lima Ferreira, Gonçalves, Raoni Schroeder B
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Sprache:eng
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Zusammenfassung:Leishmaniasis is a neglected tropical disease caused by Leishmania 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 Leishmania amazonensis of nine 4,8-dimethoxynaphthalenyl chalcones. Compound ((E)-1-(4,8-dimethoxynaphthalen-1-yl)-3-(4-nitrophenyl)prop-2-en-1-one), 4f, was the most promising with an IC[sub.50] = 3.3 ± 0.34 μM (promastigotes), a low cytotoxicity profile (CC[sub.50] = 372.9 ± 0.04 μM), and a high selectivity index (SI = 112.6). Furthermore, 4f 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 4f reduced the number of infected macrophages and the number of amastigotes per macrophage, with an IC[sub.50] 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.
ISSN:2079-6382
2079-6382
DOI:10.3390/antibiotics11101402