Antileishmanial activity of synthetic analogs of the naturally occurring quinolone alkaloid N-methyl-8-methoxyflindersin

• Published in: PloS one 2020-12, Vol.15 (12), p.e0243392
• Main Authors: Torres Suarez, Elaine, Granados-Falla, Diana Susana, Robledo, Sara María, Murillo, Javier, Upegui, Yulieth, Delgado, Gabriela
• Format: Article
• Language: English
• Subjects: Acids; Alkaloids; Alkaloids - pharmacology; Amastigotes; Analogs; Animals; Antiparasitic agents; Antiprotozoal Agents - chemistry; Antiprotozoal Agents - pharmacology; Apoptosis; Biocompatibility; Biology and Life Sciences; Cricetinae; Cutaneous leishmaniasis; Cytotoxicity; Disease Models, Animal; Drug therapy; Hamsters; Health aspects; Heterocyclic Compounds, 3-Ring - chemistry; Heterocyclic Compounds, 3-Ring - pharmacology; Humans; Immunomodulation; Intracellular; Leishmania; Leishmania guyanensis - drug effects; Leishmania guyanensis - pathogenicity; Leishmaniasis; Leishmaniasis, Cutaneous - drug therapy; Leishmaniasis, Cutaneous - parasitology; Leishmaniasis, Cutaneous - pathology; Macrophages; Macrophages - drug effects; Macrophages - parasitology; Medicine and Health Sciences; Metabolites; Mice; Monocytes; Necrosis; Nitric oxide; Nitric Oxide - genetics; Parasites; Parasitic diseases; Peripheral blood; Physical Sciences; Plant Leaves - chemistry; Promastigotes; Protozoa; Quinoline; Quinolines - chemistry; Quinolones; Quinolones - pharmacology; Regression analysis; Rutaceae - chemistry; Secondary metabolites; Toxicity; Tropical diseases; Ultrastructure; Vector-borne diseases
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0243392

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 [EC50], respectively) and amastigotes (5.07, 7.94, and 1.91 μg/mL EC50, 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.