Diterpenoid Alkaloid Derivatives as Potential Chemotherapeutic Agents in American Trypanosomiasis

Abstract

The use of natural products for the treatment of protozoal infections (Leishmania and Trypanosoma spp.) is well known and has been documented since ancient times. We have already established an in vitro culture system using mammalian host cells (Vero) infected with Trypanosoma cruzi in which the time course of parasite growth is determined quantitatively. This system was used to screen anti-T. cruzi agents using two experimental models: simultaneous cell infection and compound addition or preincubation of the parasite with the test compound prior to cell infection. Among 64 diterpenoid alkaloids tested, including C₁₉ and C₂₀ skeletons, five C₂₀ compounds were active on T. cruzi epimastigotes: azitine, isoazitine and 15,22-O-diacetyl-19-oxodihydroatisine had moderate effects on the parasite, while atisinium chloride and 13-oxocardiopetamine were potent T. cruzi epimastigote growth inhibitors with activity levels similar to that of benznidazole, used as the reference drug. Additionally, these compounds decreased the ability of metacyclic forms to invade mammalian cells, their intracellular replications and their transformation into trypomastigotes, with no toxicity to the host cell. These results suggest that these alkaloids are structural leads of clinically active compounds against T. cruzi and probably other members of the Trypanosomatidae.

Structural diversity and defensive properties of diterpenoid alkaloids

“…These authors did not detect any activity for atisinium chloride (59) probably due to the different method used to detect parasite viability (MTT method), Leishmania infantum was more sensitive to DAs 64, 65 and 56 than T. cruzi, suggesting species-related selectivity for the antiparasitic action of these compounds (Gonzá lez et al 2005). However, none of the 43 NDAs tested on T. cruzi or L. infantum affected parasite viability (Gonzá lez-Coloma et al 2004a;Gonzá lez et al 2006), indicating a strong molecular selectivity for the trypanocidal and leishmanicidal effect of DAs (C 20 vs. C 19 alkaloids).…”

“…In this article, we present a comparative overview of the insecticidal effects (antifeedant and toxic) on Spodoptera littoralis and Leptinotarsa decemlineata, the cytotoxicity on several tumoral cell lines with varying multidrug resistance mechanisms (CT26, SW480, HeLa, SkMel25 and SkMel28), and the antiparasitic effects against Trypanososma cruzi and Leishmania infantum of 67 diterpenoid alkaloids (44 NDAs, and 23 DAs) from several chemical classes (Gonzá lez-Coloma et al 1998, 2004aGonzá lez et al 2005Gonzá lez et al , 2006De Iné s et al 2006), isolated from Aconitum, Delphinium and Consolida species (citations in Gonzá lez-Coloma et al 1998, 2004aDe la Fuente and Reina 1990). …”

Antiplasmodial activity of atisinium chloride from the Bhutanese medicinal plant, Aconitum orochryseum

“…The antiplasmodial activity of atisinium chloride has not been reported previously, although it is known to be a potent growth inhibitor of the pathogenic protozoan, Trypanosoma cruzi (Gonzalez et al, 2006). While in vivo activity studies would still need to be undertaken, it represents a potential new antimalarial structural lead, particularly as it does not show mammalian cell toxicity (Gonzalez-Coloma et al, 2004), although in vivo toxicity (i.v.)…”

Evaluación in vitro de la actividad anti Trypanosoma cruzi de aceites esenciales de diez plantas medicinales

“…Se ha reportado que el extracto de la hoja de B. dracunculifolia, a una concentración de 3 mg/mL, produjo 100% de lisis de formas tripomastigotes de T. cruzi (13) ; los extractos y fracciones de A. amazonicus mostraron lisis de las formas tripomasigotes de T. cruzi in vitro (14) ; otros investigadores también han demostrado el efecto tripanocida de diversos extractos vegetales (10,15,16) , así como de diversas estructuras terpénicas contra uno o todos los estadíos de T. cruzi (17)(18)(19)(20) . También han mostrado efecto tripanocida algunos alcaloides (21)(22)(23) , flavonoides (24)(25)(26) , lignanos (27) y artemisininas (28) .…”