School of Pharmacy, Lanzhou University, Lanzhou, 730000, People's Republic of China.
School of Pharmacy, Lanzhou University, Lanzhou, 730000, People's Republic of China; State Key Laboratory of Grassland Agro-ecosystems, Lanzhou University, Lanzhou, 730000, China.
Eur J Med Chem. 2022 Jan 5;227:113937. doi: 10.1016/j.ejmech.2021.113937. Epub 2021 Oct 21.
Evodiamine and rutaecarpine are two alkaloids isolated from traditional Chinese herbal medicine Evodia rutaecarpa, which have been reported to have various biological activities in past decades. To explore the potential applications for evodiamine and rutaecarpine alkaloids and their derivatives, various kinds of evodiamine and rutaecarpine derivatives were designed and synthesized. Their antifungal profile against six phytopathogenic fungi Rhizoctonia solani, Botrytis cinerea, Fusarium graminearum, Fusarium oxysporum, Sclerotinia sclerotiorum, and Magnaporthe oryzae were evaluated for the first time. Furthermore, a series of modified imidazole derivatives of rutaecarpine were synthesized to investigate the structure-activity relationship. The results of antifungal activities in vitro showed that imidazole derivative of rutaecarpine A1 exhibited broad-spectrum inhibitory activities against R. solani, B. cinerea, F. oxysporum, S. sclerotiorum, M. oryzae and F. graminearum with EC values of 1.97, 5.97, 12.72, 2.87 and 16.58 μg/mL, respectively. Preliminary mechanistic studies showed that compound A1 might cause mycelial abnormalities of S. sclerotiorum, mitochondrial distortion and swelling, and inhibition of sclerotia formation and germination. Moreover, the curative effects of compound A1 were 94.7%, 81.5%, 80.8%, 65.0% at 400, 200, 100, 50 μg/mL in vivo experiments, which was far more effective than the positive control azoxystrobin. Significantly, no phytotoxicity of compound A1 on oilseed rape leaves was observed obviously even at a high concentration of 400 μg/mL. Therefore, compound A1 is expected to be a novel leading structure for the development of new antifungal agents.
吴茱萸碱和吴茱萸卡品碱是从传统中药吴茱萸中分离得到的两种生物碱，过去几十年里，它们被报道具有多种生物活性。为了探索吴茱萸碱和吴茱萸卡品碱及其衍生物的潜在应用，设计并合成了各种吴茱萸碱和吴茱萸卡品碱衍生物。首次评价了它们对 6 种植物病原菌（茄腐镰孢菌、灰葡萄孢菌、禾谷镰刀菌、尖孢镰刀菌、核盘菌和稻瘟病菌）的抗真菌谱。此外，还合成了一系列吴茱萸卡品碱的改性咪唑衍生物，以研究结构-活性关系。体外抗真菌活性结果表明，吴茱萸卡品碱 A1 的咪唑衍生物对 R. solani、B. cinerea、F. oxysporum、S. sclerotiorum、M. oryzae 和 F. graminearum 具有广谱抑制活性，EC 值分别为 1.97、5.97、12.72、2.87 和 16.58μg/mL。初步的机制研究表明，化合物 A1 可能导致 S. sclerotiorum 菌丝体异常、线粒体变形和肿胀，并抑制菌核形成和萌发。此外，在体内实验中，化合物 A1 在 400、200、100、50μg/mL 时的治疗效果分别为 94.7%、81.5%、80.8%和 65.0%，明显优于阳性对照肟菌酯。值得注意的是，即使在 400μg/mL 的高浓度下，化合物 A1 对油菜叶片也没有明显的植物毒性。因此，化合物 A1 有望成为开发新型抗真菌剂的新型先导结构。
