In Vitro and In Vivo Studies of the Utility of Dimethyl and Diethyl Carbaporphyrin Ketals in Treatment of Cutaneous Leishmaniasis

Abstract

Carbaporphyrin ketals are porphyrinoid compounds in which a pyrrole ring of a typical porphyrin macrocycle has been replaced by a ketal-substituted indene ring. It was recently demonstrated that these compounds are effective in vitro against Leishmania tarentolae. Their in vitro effectiveness is increased when they are exposed to visible light; they act as photosensitizers capable of mediating the production of reactive oxygen species (ROS). Following on this evidence, the effectiveness and cytotoxicity of the dimethyl and diethyl carbaporphyrin ketals (CKOMe and CKOEt, respectively) were determined in vitro using pathogenic Leishmania species with and without exposure to visible light (2 and 4 h). The effectiveness against various pathogenic Leishmania species was determined to be in a micromolar range. Additionally, the effect of encapsulating the carbaporphyrin ketals in liposome formulations was tested. Liposomal delivery diminished their toxicity, while the effectiveness was enhanced upon exposure to visible light (photodynamic effect). The cytotoxicity levels for human U937 cells and hamster peritoneal macrophages were in the ranges of 0.3 to 9 M and 7 to 330 M, respectively. When tested in vivo, using a hamster (Mesocricetus auratus) model of cutaneous leishmaniasis, CKOMe was active even in the dark, suggesting that the compound, once metabolized in the animal tissue, produces an active ingredient that does not seem to be photosensitive. Reduction in lesion size, histopathologic analyses, and smears confirmed the in vivo effectiveness of the compound, since the parasitic load was diminished without noticeable toxic effects.

Acumulación celular y el efecto de anti-Leishmania de protoporfirina IX exógena y endógena después del tratamiento fotodinámico

“…L. (L.) infantum promastigotes were more photosensitive to exogenous PpIX than L. (V.) panamensis promastigotes, demonstrating once again the interspecies intrinsic variation in drug sensitivity showed by some antileishmanial drugs, such as miltefosine, to which L. donovani (the main species involved in Old World leishmaniasis) was more sensitive than other Leishmania species. Leishmania parasites have been photosensitive to different exogenous photosensitizers like Al and Zn phthalocyanines, carboporphyrins, and benzophenoxazine (10,16,25,26).…”

“…PDT by ALA and MAL-induced porphyrin in the host cells could mediate the death of intracellular parasites probably due to host cell destruction. The response of L. (L.) infantum and L. (V.) panamensis to ALA-PDT showed some similarities with the response induced by ALA-PDT on L. major parasites (16). However, differences in the active doses have to be taken into account in case of a formulation for topical treatment of New Word Leishmania species.…”

Antiprotozoal activity and cytotoxicity of extracts from Solanum arboreum and S. ovalifolium (Solanaceae)

“…The activity of extracts was evaluated on intracellular amastigotes of L. (V) panamensis transfected with the green fluorescent protein gene (MHOM/CO/87/UA140pIR-GFP) (Taylor et al, 2011). Effect of each extract was determined according to the inhibition of the infection evidenced by both decrease of the infected cells and decrease of intracellular parasite load.…”

Synthesis, Leishmanicidal and Cytotoxic Activity of Triclosan-Chalcone, Triclosan-Chromone and Triclosan-Coumarin Hybrids

“…The leishmanicidal activity and cytotoxicity of the synthesized compounds was evaluated following previously reported method [40,41]. Leishmanicidal activity was reported as percentage of inhibition at 20 µg/mL and 50% effective concentration (EC 50 ) values.…”