Previous research from our group has demonstrated that marine and 2-acetylenic fatty acids display considerable antileishmanial properties by inhibiting key enzymes in Leishmania. Many marine derived fatty acids, mainly from sponges, possess vinylic halogenated moieties (bromo or chloro) but their assessment as antileishmanial candidates remains elusive even though many of these halogenated compounds display cytotoxic properties. In this work, we undertook the first total synthesis of a novel series of 2-allyl-3-halo-2-nonadecenoic acids, which preferentially inhibit the Leishmania DNA topoisomerase IB enzyme (LTopIB), enzymes that are validated targets for the development of antiparasitic drugs. However, no clear structure activity relationships (SAR) exist for the interaction of drugs, particularly fatty acids, against these type IB topoisomerases. The synthesis of the new halogenated compounds was possible by means of a palladium catalyzed haloallylation of the 2-nonadecynoic acid using either allyl bromide or allyl chloride in the presence of PdCl2(PhCN)2 in hexane. Among the new halogenated synthetic compounds, the 2-allyl-3-bromo-2-nonadecenoic acid proved to be quite inhibitory of LTopIB with an EC50 = 7 µM. This enhanced inhibition could be rationalized in terms of a halogen bond between the acid and amino acids at the active site of the enzyme. The brominated analog displayed preferential cytotoxicity towards L. infantum amastigotes with an EC50 = 2.5 µM. The total synthesis of this novel series of fatty acids, their topoisomerase IB inhibitory activities as well as their antileishmanial potential against Leishmania infantum amastigotes and promastigotes will be presented and discussed.

Synthesis of novel brominated and chlorinated vinylic fatty acids as effective inhibitors of the Leishmania topoisomerase IB enzyme

256th National Meeting (2018)

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