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

Elaine Torres Suarez,Javier Murillo,Gabriela Delgado,Diana Susana Granados-Falla,Yulieth Upegui,Sara María Robledo,Henk D F H Schallig

doi:10.1371/journal.pone.0243392

Elaine Torres Suarez, Javier Murillo + Show 5 more

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https://doi.org/10.1371/journal.pone.0243392

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Abstract

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.

Highlights

Leishmaniasis is a neglected, parasitic tropical disease caused by an intracellular protozoan from the genus Leishmania
More than 300 million people are at risk of infection, with at least 1.3 million cases documented annually, 90% of them being related to cutaneous leishmaniasis (CL) [1, 2]
No significant changes in nitric oxide (NO) production in L. (V) panamensis-infected human peripheral blood (monocyte)-derived macrophages (hMDMs) were observed 48 h posttreatment; we found an increase in NO production in infected hMDMs 72 h posttreatment with compound 1 (Fig 6)

Summary

Introduction

Leishmaniasis is a neglected, parasitic tropical disease caused by an intracellular protozoan from the genus Leishmania. Oral administration of miltefosine or intravenous administration of amphotericin B is a second therapeutic possibility [5, 6]. These drugs have adverse effects, such as cardiotoxicity, hepatic damage, nephrotoxicity, or even teratogenicity (after miltefosine administration) [7, 8]. There is a need for new therapeutic alternatives that are more effective and efficient in terms of parasite elimination and disease resolution and that are safer for patients in terms of better adherence and fewer toxic effects [10, 11]

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