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

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.

High Selectivity of 8-Hydroxyquinoline on Leishmania (Leishmania) and Leishmania (Viannia) Species Correlates with a Potent Therapeutic Activity In Vivo

“…Although animals treated with glucantime exhibited a significative decrease in lesion size and low parasitism, in the histopathology analysis, amastigote forms could be easily recognized, which, in turn, had a correlation with a significant inflammatory response, composed of macrophages with a low number of amastigote forms. Corroborating our results, a previous study showed that synthetic quinoline alkaloids were active in hamsters infected with L. (V.) panamensis and in histopathological studies, it was observed that there was a significant reduction in the inflammatory infiltrate in comparison with the non-treated animals [54], suggesting that the high leishmanicidal activity induced by quinolines leads to a reduction in the inflammatory infiltrate.…”

Antileishmanial Activity, Toxicity and Mechanism of Action of Complexes of Sodium Usnate with Lanthanide Ions: Eu(III), Sm(III), Gd(III), Nd(III), La(III) and Tb(III)

“…Although they did not meet the SI ≥ 10 criteria, both showed a potent effect on L. (L.) amazonensis amastigotes. Súarez et al obtained similar results [41] working with synthetic analogs of quinolones and alkaloids (1,2,3,4-tetrahidro(benzo)-3-quinolin-ol and 2-amino-8-hidroxiquinoline), with SI~5.0. Indeed, the application of the SI criterion is controversial for in vitro tests used in drug research for infectious diseases [40].…”

“…Indeed, the application of the SI criterion is controversial for in vitro tests used in drug research for infectious diseases [ 40 ]. Once in in vivo tests, these compounds induced a total reduction of lesions and no cytotoxicity-related clinical effects [ 41 ].…”

Evolution of the Quinoline Scaffold for the Treatment of Leishmaniasis: A Structural Perspective

“…Nevertheless, one could still assess that the effect promoted by the introduction of a methyl group is most accentuated that the one induced by a hydroxy group. By the end of 2020, Suarez et al used in silico techniques to identify synthetic quinoline alkaloids with a structure similar to the natural product N-methyl-8-methoxyflindersine and evaluated them against L. (V.) panamensis promastigotes and amastigotes [63]. The results demonstrated that, from the entire list of evaluated derivatives, only one (77, Figure 29) presents considerable levels of antileishmanial activity (IC 50 [promastigotes] = 10.0 ± 4.7 µM and IC 50 [amastigotes] = 6.6 ± 2.6 µM) and low levels of toxicity (SI = 5.5).…”