2-Octadecynoic acid as a dual life stage inhibitor of Plasmodium infections and plasmodial FAS-II enzymes

Autor(es)

Carballeira, Nestor M. ^[1] ; Bwalya, Angela Gono ^[2] ; Itoe, Maurice Ayamba ^[3] ; Andricopulo, Adriano D. ^[4] ; Cordero-Maldonado, Maria Lorena ^[5] ; Kaiser, Marcel ^{[6, 7]} ; Mota, Maria M. ^[3] ; Crawford, Alexander D. ^[5] ; Guido, Rafael V. C. ^[4] ; Tasdemir, Deniz ^{[2, 8]}

Afiliação do(s) autor(es)

^[1] Univ Puerto Rico, Dept Chem, San Juan, PR 00931 - USA

^[2] Univ London, Sch Pharm, Dept Biol & Pharmaceut Chem, London WC1N 1AX - England

^[3] Univ Lisbon, Inst Mol Med, P-1649028 Lisbon - Portugal

^[4] Univ Sao Paulo, Inst Fis Sao Carlos, Ctr Pesquisa & Inovacao Biodiversidade & Farmacos, Lab Quim Med & Computac, BR-13563120 Sao Carlos, SP - Brazil

^[5] Univ Luxembourg, Luxembourg Ctr Syst Biomed, Chem Biol Grp, L-4362 Esch Sur Alzette - Luxembourg

^[6] Univ Basel, CH-4003 Basel - Switzerland

^[7] Swiss Trop & Publ Hlth Inst, Dept Med Parasitol & Infect Biol, CH-4002 Basel - Switzerland

^[8] Natl Univ Ireland, Sch Chem, Galway - Ireland

• Tipo de documento: Artigo Científico
• Fonte: Bioorganic & Medicinal Chemistry Letters; v. 24, n. 17, p. 4151-4157, SEP 1 2014.
• Citações Web of Science: 5

Resumo

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 mu g/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 mu g/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. (C) 2014 Elsevier Ltd. All rights reserved. (AU)

• Processo FAPESP: 13/07600-3 - CIBFar - Centro de Inovação em Biodiversidade e Fármacos
• Beneficiário: Glaucius Oliva
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs