Tuberculosis is the main cause of death from a single infectious agent. Globally, according to the World Health Organization, in 2018, there were an estimated 1.2 million tuberculosis deaths. Moreover, there is a continuous appearance of drug-resistant strains. Thus, development of new antituberculosis medicines should receive high priority. Plant-derived natural products are promising candidates for this purpose. We therefore screened alkaloid extracts obtained from the root and stem barks of the Mexican Apocynaceae species Tabernaemontana alba and Tabernaemontana arborea, as well as the pure alkaloids ibogaine, voacangine, and voacamine, tested for activity against Mycobacterium tuberculosis H37Rv and cytotoxicity to mammalian Vero cells using the resazurin microtiter and the MTT assays, respectively. The extracts were analyzed by GC-MS and HPLC-UV. T. arborea root bark alkaloid extract showed the highest activity against M. tuberculosis (MIC100 = 7.8 µg/mL) of the four extracts tested. HPLC suggested that voacangine and voacamine were the major components. The latter was isolated by column chromatography, and its chemical structure was elucidated by 1H and 13C NMR, and MS. Unambiguous assignation was performed by HSQC, HMBC, and NOESY experiments. Voacamine is a dimeric bis-indole-type alkaloid and is 15 times more potent than the monomeric ibogan-type alkaloids ibogaine and voacangine (MIC100 = 15.6, 250.0, and 250.0 µg/mL, respectively). However, all of these compounds showed cytotoxicity to Vero cells, with a poor selectivity index of 1.00, 0.16, and 1.42, respectively. This is the first report of voacamine activity against M. tuberculosis.

中文翻译：

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Tabernaemontana alba 和 T. arborea 生物碱和提取物的抗分枝杆菌活性

结核病是单一传染源导致死亡的主要原因。根据世界卫生组织的数据，2018 年全球估计有 120 万人死于结核病。而且，耐药菌株不断出现。因此，新的抗结核药物的开发应受到高度重视。植物源性天然产品是用于此目的的有希望的候选者。因此，我们筛选了从墨西哥夹竹桃科植物 Tabernaemontana alba 和 Tabernaemontana arborea 的根和茎皮中提取的生物碱提取物，以及纯生物碱 ibogaine、voacangine 和 voacamine，并使用该方法测试了其抗结核分枝杆菌 H37Rv 的活性以及对哺乳动物 Vero 细胞的细胞毒性。分别进行刃天青微量滴定和MTT测定。通过 GC-MS 和 HPLC-UV 分析提取物。在所测试的四种提取物中，木香树根皮生物碱提取物对结核分枝杆菌表现出最高的活性（MIC100 = 7.8 µg/mL）。HPLC表明voacangine和voacamine是主要成分。后者通过柱色谱分离，其化学结构通过1H和13C NMR以及MS阐明。通过 HSQC、HMBC 和 NOESY 实验进行明确分配。Voacamine 是一种二聚双吲哚型生物碱，比单体 ibogan 型生物碱 ibogaine 和 voacangine 效力强 15 倍（MIC100 分别 = 15.6、250.0 和 250.0 µg/mL）。然而，所有这些化合物均对 Vero 细胞表现出细胞毒性，选择性指数较差，分别为 1.00、0.16 和 1.42。这是 voacamine 对抗结核分枝杆菌活性的第一份报告。