Antiprotozoal Structure–Activity Relationships of Synthetic Leucinostatin Derivatives and Elucidation of their Mode of Action

Leucinostatin A is one of the most potent antiprotozoal compounds ever described, but little was known on structure–activity relationships (SAR). We used Trypanosoma brucei as a protozoal model organism to test synthetically modified derivatives, resulting in simplified equally active 2 (ZHAWOC6025) and 4 (ZHAWOC6027), which were subsequently all regions molecule gain an in-depth SAR understanding. The matched phospholipid liposomes, where membrane integrity, leaking, dynamics studied. mode action discussed based analysis derivatives efficacy, ultrastructural studies T. brucei, artificial models, mimicking stability potential. main site natural synthetic leucinostatins lies destabilization inner mitochondrial membrane, demonstrated by analysis, electron microscopy staining. Long-time sublethal exposure (200 passages) siRNA screening 12′000 mutants showed no signs resistance development derivatives.