Synthesis of a novel brominated vinylic fatty acid with antileishmanial activity that effectively inhibits the topoisomerase IB enzyme mediated by halogen bond formation.

Many marine derived fatty acids, mainly from sponges, possess vinylic halogenated moieties (bromine or iodine) but their assessment as antileishmanial candidates remains elusive. 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 DNA topoisomerase IB enzyme (TopIB) over the human topoisomerase IB enzyme (hTopIB). The synthesis of 2-allyl-3-bromo-2-nonadecenoic acid () and 2-allyl-3-chloro-2-nonadecenoic acid () was achieved through a palladium catalyzed haloallylation of 2-nonadecynoic acid (2-NDA) using either allyl bromide or allyl chloride in the presence of PdCl(PhCN) in 57-83 % overall yields. Among the new halogenated synthetic compounds, was the most inhibitory of TopIB with an EC = 7 μM, while the shorter chain analogs 2-allyl-3-bromo-2-dodecenoic acid () and 2-allyl-3-chloro-2-dodecenoic acid (), synthesized from 2-dodecynoic acid, were not inhibitory of TopIB (EC > 100 μM) resulting in the overall order of inhibition  > 2-NDA >  > >  ≅ . The acids and inhibit TopIB by a Gimatecan-independent mechanism. The enhanced TopIB inhibition of was computationally rationalized in terms of a halogen bond between the bromine in and a DNA phosphate (binding energy = - 4.85 kcal/mol). Acid also displayed preferential cytotoxicity towards amastigotes (EC = 2.5 μM) over promastigotes (EC > 25 μM).