2-Alkynoic fatty acids inhibit topoisomerase IB from Leishmania donovani

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Abstract

2-Alkynoic fatty acids display antimycobacterial, antifungal, and pesticidal activities but their antiprotozoal activity has received little attention. In this work we synthesized the 2-octadecynoic acid (2-ODA), 2-hexadecynoic acid (2-HDA), and 2-tetradecynoic acid (2-TDA) and show that 2-ODA is the best inhibitor of the Leishmania donovani DNA topoisomerase IB enzyme (LdTopIB) with an EC50 = 5.3 ± 0.7 μM. The potency of LdTopIB inhibition follows the trend 2-ODA > 2-HDA > 2-TDA, indicating that the effectiveness of inhibition depends on the fatty acid carbon chain length. All of the studied 2-alkynoic fatty acids were less potent inhibitors of the human topoisomerase IB enzyme (hTopIB) as compared to LdTopIB. 2-ODA also displayed in vitro activity against Leishmania donovani (IC50 = 11.0 μM), but it was less effective against other protozoa, Trypanosoma cruzi (IC50 = 48.1 μM) and Trypanosoma brucei rhodesiense (IC50 = 64.5 μM). The antiprotozoal activity of the 2-alkynoic fatty acids, in general, followed the trend 2-ODA > 2-HDA > 2-TDA. The experimental information gathered so far indicates that 2-ODA is a promising antileishmanial compound.

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Acknowledgments

The project described was supported by Award Number SC1GM084708 from the National Institutes of General Medical Sciences of the NIH. M. Cartagena thanks the UPR RISE program for a graduate fellowship. We thank Gabriel Cintrón for technical assistance. This research was also supported in part by Ministerio de Ciencia e Innovation (Grant AGL2010-16078/GAN), by Junta de Castilla y León (Grant Gr-238) and Instituto de Salud Carlos III (Grant PI09/0448 and the Tropical Diseases Network RICET) from

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