title: 2-Alkynoic fatty acids inhibit topoisomerase IB from Leishmania donovani.
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 EC(50)=5.3±0.7μM. 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 (IC(50)=11.0μM), but it was less effective against other protozoa, Trypanosoma cruzi (IC(50)=48.1μM) and Trypanosoma brucei rhodesiense (IC(50)=64.5μM). 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.
authors.affiliation: Department of Chemistry, University of Puerto Rico, PO Box 23346, San Juan 00931-3346, Puerto Rico. nestor.carballeira1@upr.edu
authors.forename: Néstor M
authors.initials: NM
authors.lastname: Carballeira
authors.forename: Michelle
authors.initials: M
authors.lastname: Cartagena
authors.forename: David
authors.initials: D
authors.lastname: Sanabria
authors.forename: Deniz
authors.initials: D
authors.lastname: Tasdemir
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Prada
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Reguera
authors.forename: Rafael
authors.initials: R
authors.lastname: Balaña-Fouce
mesh_terms: D000480:Alkynes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005231:Fatty Acids, Unsaturated / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects / Q000201:enzymology*; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D051381:Rats; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects; D014349:Trypanosoma cruzi / Q000187:drug effects
chemical_list: C511879:2-octadecynoic acid; C577892:2-tetradecynoic acid; D000480:Alkynes; D000981:Antiprotozoal Agents; D005231:Fatty Acids, Unsaturated; D059004:Topoisomerase I Inhibitors; C031203:2-hexadecynoic acid; D004264:DNA Topoisomerases, Type I