Diterpenoid alkaloid derivatives as potential chemotherapeutic agents in American trypanosomiasis.
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.
González
Patricia
P
Departamento de Parasitología, Instituto de Biotecnología, Facultad de Ciencias, Universidad de Granada, Granada, España.
Marín
Clotilde
C
Rodríguez-González
Isabel
I
Illana
Antonio
A
Mateo
Hector
H
Longoni
Silvia Stefánia
SS
Rosales
María Jose
MJ
González-Coloma
Azucena
A
Reina
Matías
M
Sánchez-Moreno
Manuel
M
D000470:Alkaloids / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity*; D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy; D002522:Chlorocebus aethiops; D004224:Diterpenes / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity*; D020128:Inhibitory Concentration 50; D009593:Nitroimidazoles / Q000633:toxicity; D021261:Parasitic Sensitivity Tests / Q000379:methods; D028321:Plant Preparations / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D013997:Time Factors; D014344:Trypanocidal Agents / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000254:growth & development; D014709:Vero Cells
C509542:13-oxocardiopetamine; C509540:15,22-O-diacetyl-19-oxodihydroatisine; D000470:Alkaloids; D004224:Diterpenes; D009593:Nitroimidazoles; D028321:Plant Preparations; D014344:Trypanocidal Agents; C509541:atisinium chloride; C414609:isoazitine; C009999:benzonidazole