Open AccessAntileishmanial activity of synthetic analogs of the naturally occurring quinolone alkaloid N-methyl-8-methoxyflindersin
Author(s) -
Elaine Torres Suarez,
Diana Granados-Falla,
Sara M. Robledo,
Javier Murillo,
Yulieth Upegui,
Gabriela Delgado
Publication year - 2020
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0243392
Subject(s) - amastigote , leishmania , antiparasitic , biology , cutaneous leishmaniasis , quinoline , antiparasitic agent , pharmacology , intracellular parasite , leishmania major , leishmaniasis , intracellular , microbiology and biotechnology , biochemistry , chemistry , immunology , medicine , parasite hosting , pathology , organic chemistry , world wide web , computer science
Leishmaniasis is a neglected, parasitic tropical disease caused by an intracellular protozoan from the genus Leishmania . Quinoline alkaloids, secondary metabolites found in plants from the Rutaceae family, have antiparasitic activity against Leishmania sp. N -methyl-8-methoxyflindersin ( 1 ), isolated from the leaves of Raputia heptaphylla and also known as 7-methoxy-2,2-dimethyl-2H,5H,6H-pyran[3,2-c]quinolin-5-one, shows antiparasitic activity against Leishmania promastigotes and amastigotes. This study used in silico tools to identify synthetic quinoline alkaloids having structure similar to that of compound 1 and then tested these quinoline alkaloids for their in vitro antiparasitic activity against Leishmania (Viannia) panamensis , in vivo therapeutic response in hamsters suffering from experimental cutaneous leishmaniasis (CL), and ex vivo immunomodulatory potential in healthy donors’ human peripheral blood (monocyte)-derived macrophages (hMDMs). Compounds 1 (natural), 2 (synthetic), and 8 (synthetic) were effective against intracellular promastigotes (9.9, 3.4, and 1.6 μg/mL medial effective concentration [EC 50 ], respectively) and amastigotes (5.07, 7.94, and 1.91 μg/mL EC 50 , respectively). Compound 1 increased nitric oxide production in infected hMDMs and triggered necrosis-related ultrastructural alterations in intracellular amastigotes, while compound 2 stimulated oxidative breakdown in hMDMs and caused ultrastructural alterations in the parasite 4 h posttreatment, and compound 8 failed to induce macrophage modulation but selectively induced apoptosis of infected hMDMs and alterations in the intracellular parasite ultrastructure. In addition, synthetic compounds 2 and 8 improved the health of hamsters suffering from experimental CL, without evidence of treatment-associated adverse toxic effects. Therefore, synthetic compounds 2 and 8 are potential therapeutic candidates for topical treatment of CL.