Total Synthesis and Antileishmanial Activity of the Natural Occurring Acetylenic Fatty Acids 6-Heptadecynoic Acid and 6-Icosynoic Acid

Abstract

The first total syntheses of the naturally occurring acetylenic fatty acids—6-heptadecynoic acid (59% overall yield) and 6-icosynoic acid (34% overall yield)—was accomplished in four steps. Using the same synthetic sequence the naturally occurring fatty acids (6Z)-heptadecenoic acid (46% overall yield) and (6Z)-icosenoic acid (27% overall yield) were also synthesized. The Δ⁶ acetylenic fatty acids displayed good antiprotozoal activity towards Leishmania donovani promastigotes (EC₅₀ = 1–6 µg/mL), but the 6-icosynoic acid was the most effective in the series. In addition, the (6Z)-icosenoic acid was a much better antiprotozoal compound (EC₅₀ = 5–6 µg/mL) than the (6Z)-heptadecenoic acid (EC₅₀ > 25 µg/mL). The saturated fatty acids n-heptadecanoic acid and n-eicosanoic acid were not effective towards L. donovani, indicating that the Δ⁶ unsaturation in these fatty acids is necessary for leishmanicidal activity. In addition, both the 6-icosynoic acid and the (6Z)-icosenoic acid were inhibitors of the Leishmania DNA topoisomerase IB enzyme (EC_50’s = 36–49 µM), a possible intracellular target for these compounds. This is the first study assessing fatty acids as inhibitors of the Leishmania DNA topoisomerase IB enzyme.