Faculty of Science, Department of Chemistry, Rhodes University, Grahamstown, 6140, South Africa.
Faculty of Science, Department of Biochemistry and Microbiology, Rhodes University, Grahamstown, 6140, South Africa.
Chembiochem. 2020 Sep 14;21(18):2643-2658. doi: 10.1002/cbic.202000132. Epub 2020 May 27.
The conjugation of organometallic complexes to known bioactive organic frameworks is a proven strategy revered for devising new drug molecules with novel modes of action. This approach holds great promise for the generation of potent drug leads in the quest for therapeutic chemotypes with the potential to overcome the development of clinical resistance. Herein, we present the in vitro antiplasmodial and antiproliferative investigation of ferrocenyl α-aminocresol conjugates assembled by amalgamation of the organometallic ferrocene unit and an α-aminocresol scaffold possessing antimalarial activity. The compounds pursued in the study exhibited higher toxicity towards the chemosensitive (3D7) and -resistant (Dd2) strains of the Plasmodium falciparum parasite than to the human HCC70 triple-negative breast cancer cell line. Indication of cross-resistance was absent for the compounds evaluated against the multi-resistant Dd2 strain. Structure-activity analysis revealed that the phenolic hydroxy group and rotatable σ bond between the α-carbon and NH group of the α-amino-o-cresol skeleton are crucial for the biological activity of the compounds. Spectrophotometric techniques and in silico docking simulations performed on selected derivatives suggest that the compounds show a dual mode of action involving hemozoin inhibition and DNA interaction via minor-groove binding. Lastly, compound 9 a, identified as a possible lead, exhibited preferential binding for the plasmodial DNA isolated from 3D7 P. falciparum trophozoites over the mammalian calf thymus DNA, thereby substantiating the enhanced antiplasmodial activity of the compounds. The presented research demonstrates the strategy of incorporating organometallic complexes into known biologically active organic scaffolds as a viable avenue to fashion novel multimodal compounds with potential to counter the development drug resistance.
将有机金属配合物与已知的生物活性有机骨架连接起来，是一种经过验证的策略，可用于设计具有新型作用模式的新药物分子。这种方法为生成具有潜在治疗化学类型的有效药物先导化合物提供了很大的可能性，这些先导化合物有可能克服临床耐药性的发展。在这里，我们展示了通过将有机金属二茂铁单元和具有抗疟活性的α-氨基间甲酚支架融合而组装的二茂铁基α-氨基间甲酚缀合物的体外抗疟原虫和抗增殖研究。在所研究的化合物中，对化学敏感（3D7）和耐药（Dd2）株疟原虫寄生虫的毒性高于对人 HCC70 三阴性乳腺癌细胞系的毒性。在所评估的化合物中，没有针对多耐药 Dd2 株的交叉耐药性。结构活性分析表明，酚羟基和α-氨基邻甲酚骨架中α-碳和 NH 基团之间的可旋转σ键对于化合物的生物活性至关重要。对选定衍生物进行的分光光度技术和计算机对接模拟表明，这些化合物表现出双重作用模式，涉及亚铁血红素抑制和通过小沟结合与 DNA 相互作用。最后，鉴定为可能的先导化合物 9a 优先与 3D7 疟原虫滋养体分离的疟原虫 DNA 结合，而不是与哺乳动物小牛胸腺 DNA 结合，从而证实了化合物增强的抗疟原虫活性。所提出的研究表明，将有机金属配合物纳入已知的生物活性有机骨架中是一种可行的策略，可以设计具有潜在抗药性的新型多模态化合物。
