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

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.

seco-limonoids and quinoline alkaloids from Raputia heptaphylla and their antileishmanial activity.

A novel seco-limonoid, rel-(1S,5R,9S,7R,8S,9R,10S,11R,13S,14R,15R,17R)-11,19-dihydroxy-7-acetoxy-7-deoxoichangin (raputiolide) (1), and two novel quinolone alkaloids N-methyl-2-phenoxyquinolin-4(1H)-one (heptaphyllone A) (2) and 6-methylbenzofuro[2,3-b]quinolin-4(1H)-one (heptaphyllone B) (3), along with the known seco-limonoid ichangin (4), were isolated from Raputia heptaphylla PITTIER (Rutaceae) stem bark. Five known alkaloids, N-methyl-8-methoxyflindersine (5), skimmianine (6), kokusaginine (7), dictamnine (8) and flindersiamine (9), were also isolated from R. heptaphylla leaves. Their structures were established on the basis of full spectroscopic data interpretation supported by data from the pertinent literature. seco-Limonoid 1 configuration was determined by enhanced nuclear Overhauser effect spectroscopy (NOESY) experiments and density functional theory (DFT) molecular modeling. The antileishmanial effect of the isolated compounds was evaluated on Leishmania Viannia panamensis (promastigotes and amastigotes). Whereas alkaloids 2-3, 6-8 and limonoid 4 exhibited no significant parasitocide activity against internalized L. (V.) panamensis amastigotes, limonoid 1 and alkaloid 5 had leishmanicidal activity on intracellular amastigotes (EC50: 8.7 µg/ml) and promastigotes (EC(50): 14.3 µg/ml), respectively.