Néstor M Carballeira1, Angela Gono Bwalya2, Maurice Ayamba Itoe3, Adriano D Andricopulo4, María Lorena Cordero-Maldonado5, Marcel Kaiser6, Maria M Mota3, Alexander D Crawford5, Rafael V C Guido4, Deniz Tasdemir7. 1. Department of Chemistry, University of Puerto Rico, PO Box 23346, San Juan 00931-3346, Puerto Rico. Electronic address: nestor.carballeira1@upr.edu. 2. Department of Biological and Pharmaceutical Chemistry, University of London, School of Pharmacy, London WC1N 1AX, UK. 3. Instituto de Medicina Molecular, Universidade de Lisboa, Lisbon 1649-028, Portugal. 4. 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. 5. Chemical Biology Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4362 Esch-sur-Alzette, Luxembourg. 6. 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. 7. 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.
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.
The malariaparasite pan class="Species">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: Néstor M Carballeira; Michelle Cartagena; David Sanabria; Deniz Tasdemir; Christopher F Prada; Rosa M Reguera; Rafael Balaña-Fouce Journal: Bioorg Med Chem Lett Date: 2012-08-10 Impact factor: 2.823
Authors: Jasmine Spavieri; Andrea Allmendinger; Marcel Kaiser; Maurice Ayamba Itoe; Gerald Blunden; Maria M Mota; Deniz Tasdemir Journal: Mar Drugs Date: 2013-10-22 Impact factor: 5.118
Authors: David Kokel; Jennifer Bryan; Christian Laggner; Rick White; Chung Yan J Cheung; Rita Mateus; David Healey; Sonia Kim; Andreas A Werdich; Stephen J Haggarty; Calum A Macrae; Brian Shoichet; Randall T Peterson Journal: Nat Chem Biol Date: 2010-01-17 Impact factor: 15.040
Authors: María Álvarez-Bardón; Yolanda Pérez-Pertejo; César Ordóñez; Daniel Sepúlveda-Crespo; Nestor M Carballeira; Babu L Tekwani; Sankaranarayanan Murugesan; Maria Martinez-Valladares; Carlos García-Estrada; Rosa M Reguera; Rafael Balaña-Fouce Journal: Mar Drugs Date: 2020-03-31 Impact factor: 5.118