Carballeira Néstor M, Bwalya Angela Gono, Itoe Maurice Ayamba, Andricopulo Adriano D, Cordero-Maldonado María Lorena, Kaiser Marcel, Mota Maria M, Crawford Alexander D, Guido Rafael V C, Tasdemir Deniz
Department of Chemistry, University of Puerto Rico, PO Box 23346, San Juan 00931-3346, Puerto Rico.
Department of Biological and Pharmaceutical Chemistry, University of London, School of Pharmacy, London WC1N 1AX, UK.
Bioorg Med Chem Lett. 2014 Sep 1;24(17):4151-7. doi: 10.1016/j.bmcl.2014.07.050. Epub 2014 Jul 24.
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.
疟原虫在人类宿主中经历两个生命阶段，先是无症状的肝脏阶段（LS），随后是出现该疾病所有临床表现的血液阶段。在本研究中，我们研究了一系列碳原子数在14至18之间的2-炔酸脂肪酸（2-AFA）对这两个生命阶段的双重体外活性。2-十八碳炔酸（2-ODA）被确定为伯氏疟原虫寄生虫的最佳抑制剂，其效力比对照药物高十倍（IC50 = 0.34μg/ml）。在靶点确定研究中，同一化合物抑制三种恶性疟原虫FAS-II（PfFAS-II）延伸酶PfFabI、PfFabZ和PfFabG，IC50值最低（分别为0.28 - 0.80μg/ml）。分子建模研究深入了解了这一系列2-AFA抑制活性背后的分子机制，并对其显著不同的抑制潜力给出了可能的解释。恶性疟原虫的血液阶段呈现类似趋势，2-ODA是最具活性的化合物，但其效力低20倍。分别通过体外和体内方法在哺乳动物细胞系和斑马鱼模型中评估了2-AFA的一般毒性和肝毒性。本研究确定2-ODA是最有前景的抗寄生虫2-AFA，尤其是对伯氏疟原虫寄生虫。
