title: 2-Octadecynoic acid as a dual life stage inhibitor of Plasmodium infections and plasmodial FAS-II enzymes.
abstract: The malaria parasite Plasmodium goes through two life stages in the human host, a non-symptomatic liver stage (LS) followed by a blood stage with all clinical manifestation of the disease. In this study, we investigated a series of 2-alkynoic fatty acids (2-AFAs) with chain lengths between 14 and 18 carbon atoms for dual in vitro activity against both life stages. 2-Octadecynoic acid (2-ODA) was identified as the best inhibitor of Plasmodium berghei parasites with ten times higher potency (IC50=0.34 μg/ml) than the control drug. In target determination studies, the same compound inhibited three Plasmodium falciparum FAS-II (PfFAS-II) elongation enzymes PfFabI, PfFabZ, and PfFabG with the lowest IC50 values (0.28-0.80 μg/ml, respectively). Molecular modeling studies provided insights into the molecular aspects underlying the inhibitory activity of this series of 2-AFAs and a likely explanation for the considerably different inhibition potentials. Blood stages of P. falciparum followed a similar trend where 2-ODA emerged as the most active compound, with 20 times less potency. The general toxicity and hepatotoxicity of 2-AFAs were evaluated by in vitro and in vivo methods in mammalian cell lines and zebrafish models, respectively. This study identifies 2-ODA as the most promising antiparasitic 2-AFA, particularly towards P. berghei parasites.
authors.affiliation: Department of Chemistry, University of Puerto Rico, PO Box 23346, San Juan 00931-3346, Puerto Rico. Electronic address: nestor.carballeira1@upr.edu.
authors.forename: Néstor M
authors.initials: NM
authors.lastname: Carballeira
authors.affiliation: Department of Biological and Pharmaceutical Chemistry, University of London, School of Pharmacy, London WC1N 1AX, UK.
authors.forename: Angela Gono
authors.initials: AG
authors.lastname: Bwalya
authors.affiliation: Instituto de Medicina Molecular, Universidade de Lisboa, Lisbon 1649-028, Portugal.
authors.forename: Maurice Ayamba
authors.initials: MA
authors.lastname: Itoe
authors.affiliation: Laboratório de Química Medicinal e Computacional, Centro de Pesquisa e Inovação em Biodiversidade e Fármacos, Instituto de Física de São Carlos, Universidade de São Paulo, São Carlos, SP 13563-120, Brazil.
authors.forename: Adriano D
authors.initials: AD
authors.lastname: Andricopulo
authors.affiliation: Chemical Biology Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4362 Esch-sur-Alzette, Luxembourg.
authors.forename: María Lorena
authors.initials: ML
authors.lastname: Cordero-Maldonado
authors.affiliation: Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, CH-4002 Basel, Switzerland; University of Basel, Petersplatz 1, CH-4003 Basel, Switzerland.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.affiliation: Instituto de Medicina Molecular, Universidade de Lisboa, Lisbon 1649-028, Portugal.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Mota
authors.affiliation: Chemical Biology Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4362 Esch-sur-Alzette, Luxembourg.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Crawford
authors.affiliation: Laboratório de Química Medicinal e Computacional, Centro de Pesquisa e Inovação em Biodiversidade e Fármacos, Instituto de Física de São Carlos, Universidade de São Paulo, São Carlos, SP 13563-120, Brazil.
authors.forename: Rafael V C
authors.initials: RV
authors.lastname: Guido
authors.affiliation: Department of Biological and Pharmaceutical Chemistry, University of London, School of Pharmacy, London WC1N 1AX, UK; School of Chemistry, National University of Ireland, Galway, Ireland. Electronic address: deniz.tasdemir@nuigalway.ie.
authors.forename: Deniz
authors.initials: D
authors.lastname: Tasdemir
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D054889:Fatty Acid Synthase, Type II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology*; D008958:Models, Molecular; D010962:Plasmodium berghei / Q000187:drug effects / Q000201:enzymology*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D013329:Structure-Activity Relationship; D015027:Zebrafish
chemical_list: C511879:2-octadecynoic acid; D000962:Antimalarials; D005231:Fatty Acids, Unsaturated; D054889:Fatty Acid Synthase, Type II
keywords: 2-Octadecynoic acid; Acetylenic fatty acids; Blood stage; Liver stage; Malaria; Plasmodium; Type II fatty acid synthase
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