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

ABSTRACT: 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 but equally active compounds 2 (ZHAWOC6025) and 4 (ZHAWOC6027), which were subsequently modified in all regions of the molecule to gain an in-depth SAR understanding. The antiprotozoal SAR matched SAR in phospholipid liposomes, where membrane integrity, leaking, and dynamics were studied. The mode of action is discussed based on a structure-activity analysis of derivatives in efficacy, ultrastructural studies in T. brucei, and artificial membrane models, mimicking membrane stability and membrane potential. The main site of

SUBMITTER: Brand M 

PROVIDER: S-EPMC8360131 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature