de Barros Renilson Castro, Araujo da Costa Renato, Farias Suelem Daniella Pinho, de Albuquerque Kelly Cristina Oliveira, Marinho Andrey Moacir R, Campos Marliane Batista, Marinho Patrícia Santana Barbosa, Dolabela Maria Fani
Pharmaceutical Sciences Postgraduate Program, Federal University of Pará, Belém, PA, Brazil.
Federal Institute of Education Sciences of the State of Pará, Abaetetuba, PA, Brazil.
Front Chem. 2024 Jul 30;12:1394126. doi: 10.3389/fchem.2024.1394126. eCollection 2024.
The oil of showed leishmanicidal activity, with its activity being related to limonoids, but fatty acids are the major constituents of this oil. The present study evaluated the physicochemical, pharmacokinetic, and toxicity profiles of limonoids and fatty acids already identified in the species. Based on these results, 2 limonoids (methyl angosinlate, 6-OH-methyl angosinlate) and 2 fatty acids (arachidic acid; myristic acid) were selected for the prediction of possible targets and molecular docking. Included in this study were: Gedunin, 6α-acetoxygedunin, Methyl angosenlato, 7-deacetoxy-7-oxogedunin, Andirobin, 6-hydroxy-angolensate methyl, 17β-hydroxyazadiradione, 1,2-dihydro-3β-hydroxy-7-deacetoxy-7-oxogedunin, xyllocensin k, 11beta-Hydroxygedunin, 6α,11-11β-diacetoxygedunin, Oleic Acid, Palmitic Acid, Stearic Acid, Arachidic Acid, Myristic Acid, Palmitoleic Acid, Linoleic Acid, Linolenic Acid, and Beenic Acid. Regarding physicochemical aspects, fatty acids violated LogP, and only limonoid 11 violated Lipinski's rule. A common pharmacokinetic aspect was that all molecules were well absorbed in the intestine and inhibited CYP. All compounds showed toxicity in some model, with fatty acids being mutagenic and carcinogenic, and limonoids not being mutagenic and carcinogenic at least for rats. In in vivo models, fatty acids were less toxic. Molecular dockings were performed on COX-2 steroids (15 and 16) and hypoxia-inducible factor 1 alpha for limonoids (3,6), with this target being essential for the intracellular development of leishmania. Limonoids 3 and 6 appear to be promising as leishmanicidal agents, and fatty acids are promising as wound healers.
该植物的油具有杀利什曼原虫活性，其活性与柠檬苦素类化合物有关，但脂肪酸是这种油的主要成分。本研究评估了该物种中已鉴定出的柠檬苦素类化合物和脂肪酸的物理化学性质、药代动力学和毒性特征。基于这些结果，选择了2种柠檬苦素类化合物（甲基安哥辛酯、6-羟基甲基安哥辛酯）和2种脂肪酸（花生酸；肉豆蔻酸）进行可能靶点的预测和分子对接。本研究包括：格杜尼宁、6α-乙酰氧基格杜尼宁、甲基安哥辛酯、7-脱乙酰氧基-7-氧代格杜尼宁、安迪罗宾、6-羟基-安哥辛酯甲基、17β-羟基阿扎迪拉酮、1,2-二氢-3β-羟基-7-脱乙酰氧基-7-氧代格杜尼宁、木犀草素k、11β-羟基格杜尼宁、6α,11-11β-二乙酰氧基格杜尼宁、油酸、棕榈酸、硬脂酸、花生酸、肉豆蔻酸、棕榈油酸、亚油酸、亚麻酸和山嵛酸。在物理化学方面，脂肪酸违反了脂水分配系数（LogP），只有柠檬苦素类化合物11违反了Lipinski规则。一个共同的药代动力学方面是所有分子在肠道中吸收良好并抑制细胞色素P450（CYP）。所有化合物在某些模型中均显示出毒性，脂肪酸具有致突变性和致癌性，而柠檬苦素类化合物至少对大鼠无致突变性和致癌性。在体内模型中，脂肪酸的毒性较小。对柠檬苦素类化合物（3,6）的环氧化酶-2甾体（15和16）和缺氧诱导因子1α进行了分子对接，该靶点对利什曼原虫的细胞内发育至关重要。柠檬苦素类化合物3和6似乎有望成为杀利什曼原虫剂，脂肪酸有望成为伤口愈合剂。
