In vitro activity and mode of action of distamycin analogues against African trypanosomes.
Distamycin, a natural polyamide containing three heterocycle rings with a polar end, has inspired several groups to prepare synthetic analogues, which proved to have anti-trypanosomal and anti-tumoral activity. We describe the synthesis of bi and tri thiazoles amides that harbor different substitutions at their ends and the evaluation of their anti-Trypanosoma brucei activity. The most active compound 10b showed better biological activity (EC50 310 nM and selectivity index 16) than the control drug nifurtimox (EC50 15 μM and selectivity index 10). Studies on the mode of action show that the parasiticidal activity of 10b originates from disruption of lysosomal homeostasis, which is followed by release of redox active iron, an increase in oxidizing species and collapse of cell membrane integrity. In this respect, our study suggests that non-charged lipophylic distamycins destabilize cell membranes.
['Franco|Jaime|J|', 'Medeiros|Andrea|A|', 'Benítez|Diego|D|', 'Perelmuter|Karen|K|', 'Serra|Gloria|G|', 'Comini|Marcelo A|MA|', 'Scarone|Laura|L|']
D000349:Africa D000970:Antineoplastic Agents D002462:Cell Membrane D004214:Distamycins D008247:Lysosomes D010084:Oxidation-Reduction D013844:Thiazoles D014344:Trypanocidal Agents D014345:Trypanosoma D014346:Trypanosoma brucei brucei
Thiazole Lysosome Iron Membrane damage Trypanosoma brucei