Harmicines represent hybrid compounds composed of β-carboline alkaloid harmine and cinnamic acid derivatives (CADs). In this paper we report the synthesis of amide-type harmicines and the evaluation of their biological activity. N-harmicines 5a–f and O-harmicines 6a–h were prepared by a straightforward synthetic procedure, from harmine-based amines and CADs using standard coupling conditions, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo [4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) and N,N-diisopropylethylamine (DIEA). Amide-type harmicines exerted remarkable activity against the erythrocytic stage of P. falciparum, in low submicromolar concentrations, which was significantly more pronounced compared to their antiplasmodial activity against the hepatic stages of P. berghei. Furthermore, a cytotoxicity assay against the human liver hepatocellular carcinoma cell line (HepG2) revealed favorable selectivity indices of the most active harmicines. Molecular dynamics simulations demonstrated the binding of ligands within the ATP binding site of PfHsp90, while the calculated binding free energies confirmed higher activity of N-harmicines 5 over their O-substituted analogues 6. Amino acids predominantly affecting the binding were identified, which provided guidelines for the further derivatization of the harmine framework towards more efficient agents.

中文翻译：

---

对疟原虫具有增强效力的新型药物

Harmicines 代表由β-咔啉生物碱harmine 和肉桂酸衍生物(CADs) 组成的杂合化合物。在本文中，我们报告了酰胺类药物的合成及其生物活性的评价。N-甘草素 5a–f 和 O-甘草素 6a–h 是通过简单的合成程序制备的，使用标准偶联条件，1-[双（二甲氨基）亚甲基]-1H-1,2,3，从基于苦素的胺和 CAD -三唑并 [4,5-b] 吡啶鎓 3-氧化六氟磷酸盐 (HATU) 和 N,N-二异丙基乙胺 (DIEA)。酰胺类药物对恶性疟原虫的红细胞阶段表现出显着的活性，在低亚微摩尔浓度下，与对伯氏疟原虫肝脏阶段的抗疟原虫活性相比，这种活性显着更显着。此外，一项针对人肝肝细胞癌细胞系 (HepG2) 的细胞毒性试验揭示了最活跃的有害物质具有良好的选择性指数。分子动力学模拟证明了配体在 PfHsp90 的 ATP 结合位点内的结合，而计算的结合自由能证实 N-甘草碱 5 的活性高于其 O-取代类似物 6。鉴定了主要影响结合的氨基酸，这提供了指导用于进一步衍生化 harmine 框架，以获得更有效的代理。