Department of Chemistry, Faculty of Science, University of Maroua, Maroua P.O. Box 814, Cameroon.
Natural Product and Environmental Chemistry Group (NAPEC), Department of Chemistry, Higher Teachers' Training College, University of Maroua, Maroua P.O. Box 55, Cameroon.
Molecules. 2023 Oct 23;28(20):7227. doi: 10.3390/molecules28207227.
and sp. resistance to antiparasitic drugs has become a major concern in malaria and leishmaniasis control. These diseases are public health problems with significant socioeconomic impacts, and mostly affect disadvantaged populations living in remote tropical areas. This challenge emphasizes the need to search for new chemical scaffolds that preferably possess novel modes of action to contribute to antimalarial and antileishmanial research programs. This study aimed to investigate the antimalarial and antileishmanial properties of a methanol extract (-) of the stem bark of the Cameroonian medicinal plant and its isolated compounds. The purification of - led to the isolation of a new ordered limonoid derivative, 21-hydroxybourjotinolone A (), together with 15 known compounds (-) using a repeated column chromatography. Compound was obtained in an epimeric mixture of 21-melianodiol () and 21-melianodiol (). Structural characterization of the isolated compounds was achieved with HRMS, and 1D- and 2D-NMR analyses. The extracts and compounds were screened using pre-established in vitro methods against synchronized ring stage cultures of the multidrug-resistant Dd2 and chloroquine-sensitive/sulfadoxine-resistant 3D7 strains of and the promastigote form of (1S(MHOM/SD/62/1S). In addition, the samples were tested for cytotoxicity against RAW 264.7 macrophages. Positive controls consisted of artemisinin and chloroquine for , amphotericin B for , and podophyllotoxin for cytotoxicity against RAW 264.7 cells. The extract and fractions exhibited moderate to potent antileishmanial activity with 50% inhibitory concentrations (IC) ranging from 5.99 ± 0.77 to 2.68 ± 0.42 μg/mL, while compounds displayed IC values ranging from 81.73 ± 0.12 to 6.43 ± 0.06 μg/mL. They were weakly active against the chloroquine-sensitive/sulfadoxine-resistant 3D7 strain but highly potent toward the multidrug-resistant Dd2 (extracts, IC 2.50 ± 0.12 to 4.78 ± 0.36 μg/mL; compounds IC 2.93 ± 0.02 to 50.97 ± 0.37 μg/mL) with selectivity indices greater than 10 (SI > 10) for the extract and fractions and most of the derived compounds. Of note, the limonoid mixture [21-hydroxylbourjotinolone A () + 21-melianodiol () + 21-melianodiol ()] exhibited moderate activity against and This novel antiplasmodial and antileishmanial chemical scaffold qualifies as a promising starting point for further medicinal chemistry-driven development of a dually active agent against two major infectious diseases affecting humans in Africa.
并且，寄生虫抗药性已经成为疟疾和利什曼病控制的主要关注点。这些疾病是具有重大社会经济影响的公共卫生问题，主要影响生活在偏远热带地区的贫困人群。这一挑战强调需要寻找新的化学支架，最好具有新的作用模式，以促进抗疟和抗利什曼病的研究计划。本研究旨在调查来自喀麦隆药用植物的甲醇提取物 (-)及其分离化合物的抗疟和抗利什曼原虫特性。使用重复柱层析对 (-)进行纯化，得到了一种新的有序柠檬苦素衍生物 21-羟基布吉丁酮 A ()，以及 15 种已知化合物 (-)。化合物 是在 21-美莲二醇 ()和 21-美莲二醇 ()的差向异构体混合物中获得的。通过高分辨率质谱 (HRMS)和 1D-和 2D-NMR 分析实现了分离化合物的结构表征。使用预先建立的体外方法对提取物和化合物进行了筛选，以对抗多药耐药的 Dd2 和氯喹敏感/磺胺多辛耐药的 3D7 株和 （1S(MHOM/SD/62/1S）的同步环阶段培养物和前鞭毛体形式进行筛选。此外，还测试了样品对 RAW 264.7 巨噬细胞的细胞毒性。阳性对照由青蒿素和氯喹组成，用于 ，两性霉素 B 用于 ，鬼臼毒素用于 RAW 264.7 细胞的细胞毒性。提取物和馏分表现出中度至强效的抗利什曼原虫活性，50%抑制浓度 (IC) 范围为 5.99 ± 0.77 至 2.68 ± 0.42 μg/mL，而化合物的 IC 值范围为 81.73 ± 0.12 至 6.43 ± 0.06 μg/mL。它们对氯喹敏感/磺胺多辛耐药的 3D7 株活性较弱，但对多药耐药的 Dd2 株活性很强（提取物，IC 2.50 ± 0.12 至 4.78 ± 0.36 μg/mL；化合物 IC 2.93 ± 0.02 至 50.97 ± 0.37 μg/mL），提取物和馏分的选择性指数大于 10（SI > 10），大多数衍生化合物也是如此。值得注意的是，该柠檬苦素混合物[21-羟基布吉丁酮 A () + 21-美莲二醇 () + 21-美莲二醇 ()]对 和 表现出中等活性。这种新型的抗疟和抗利什曼原虫的化学支架是一个有前途的起点，可以进一步进行基于药物化学的双重活性药物的开发，以对抗影响非洲人类的两种主要传染病。
