National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, The University of Mississippi, University, MS 38677, USA.
Division of Pharmacognosy, Department of BioMolecular Sciences, School of Pharmacy, The University of Mississippi, University, MS 38677, USA.
Molecules. 2020 Dec 24;26(1):59. doi: 10.3390/molecules26010059.
The metabolic pathways in the apicoplast organelle of parasites are similar to those in plastids in plant cells and are suitable targets for malaria drug discovery. Some phytotoxins released by plant pathogenic fungi have been known to target metabolic pathways of the plastid; thus, they may also serve as potential antimalarial drug leads. An EtOAc extract of the broth of the endophyte isolated from a seed collected from a plant with disease symptoms, showed in vitro antimalarial and phytotoxic activities. Bioactivity-guided fractionation of the extract afforded a mixture of two known isomeric phytotoxins, FRT-A and flavipucine (or their enantiomers, sapinopyridione and (-)-flavipucine), and two new unstable -lactam alkaloids dothilactaenes A and B. The isomeric mixture of phytotoxins displayed strong phytotoxicity against both a dicot and a monocot and moderate cytotoxicity against a panel of cell lines. Dothilactaene A showed no activity. Dothilactaene B was isolated from the active fraction, which showed moderate in vitro antiplasmodial activity with high selectivity index. In spite of this activity, its instability and various other biological activities shown by related compounds would preclude it from being a viable antimalarial lead.
寄生虫类质体器官中的代谢途径与植物细胞中的质体相似，是疟疾药物发现的合适靶点。一些植物病原真菌释放的植物毒素已知靶向质体的代谢途径；因此，它们也可能成为潜在的抗疟药物先导化合物。从一株带有病症的植物种子中分离出的内生菌的发酵液的 EtOAc 提取物，表现出体外抗疟和植物毒性活性。根据提取物的生物活性指导进行的分段分离，得到了两种已知的同分异构植物毒素 FRT-A 和 flavipucine（或其对映异构体 sapinopyridione 和 (-)-flavipucine），以及两种新的不稳定β-内酰胺生物碱 dothilactaenes A 和 B。这种同分异构混合物的植物毒素对双子叶植物和单子叶植物均显示出很强的植物毒性，对一组细胞系显示出中等的细胞毒性。dothilactaene A 没有活性。从活性部分分离出 dothilactaene B，其显示出中等体外抗疟活性和高选择性指数。尽管具有这种活性，但与其相关的化合物所表现出的不稳定性和各种其他生物学活性，使其不可能成为可行的抗疟药物先导化合物。
