Golding Taryn M, Garnie Larnelle F, Rabie Tayla, Reader Janette, Birkholtz Lyn-Marié, Wicht Kathryn J, Smith Gregory S
Department of Chemistry, University of Cape Town, Rondebosch, Cape Town 7701, South Africa.
Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria Control, University of Pretoria, Hatfield 0028, South Africa.
Inorg Chem. 2025 Aug 11;64(31):16152-16167. doi: 10.1021/acs.inorgchem.5c02689. Epub 2025 Jul 31.
Molecular hybridization and metal incorporation are widely employed strategies for drug development aimed at enhancing pharmacological efficacy while mitigating the emergence of drug resistance. The effectiveness of these approaches is supported by numerous studies demonstrating their success against a range of diseases. Despite the deployment of malaria vaccines, effective treatment remains hindered by the persistent emergence of drug-resistant strains, contributing to an alarming global disease burden. Inspired by the antimalarial candidate ferroquine, this study focused on the design and synthesis of ferrocenyl-based quinoline-benzimidazole molecular hybrids. The hybrids were evaluated for their in vitro blood-stage antiplasmodial activity against drug-sensitive NF54 and multidrug-resistant K1 strains, exhibiting potent submicromolar activity. Notably, incorporating an ,-dimethylaminomethyl side chain significantly enhanced activity against both strains. Further assays revealed a compound with multistage antiplasmodial activity, targeting both immature and mature gametocytes. Mechanistic studies implicated the inhibition of hemozoin formation as a key mode of action, supported by in vitro cellular heme fractionation analysis. Additionally, fluorescence assays indicated the generation of reactive oxygen species under oxidative conditions, suggesting a complementary pathway contributing to the compounds' antiplasmodial activity. These findings highlight the potential of ferrocenyl-based molecular hybrids as promising candidates in antiplasmodial drug development.
分子杂交和金属掺入是药物开发中广泛采用的策略，旨在提高药理疗效，同时减轻耐药性的出现。这些方法的有效性得到了大量研究的支持，这些研究表明它们在对抗一系列疾病方面取得了成功。尽管部署了疟疾疫苗，但耐药菌株的持续出现仍然阻碍了有效治疗，导致全球疾病负担惊人。受抗疟候选药物铁喹啉的启发，本研究专注于基于二茂铁基喹啉 - 苯并咪唑分子杂化物的设计与合成。对这些杂化物针对药物敏感的NF54和多药耐药的K1菌株的体外血液阶段抗疟原虫活性进行了评估，显示出强效的亚微摩尔活性。值得注意的是，引入一个α，β - 二甲基氨基甲基侧链显著增强了对这两种菌株的活性。进一步的试验揭示了一种具有多阶段抗疟原虫活性的化合物，其靶向未成熟和成熟配子体。机制研究表明抑制疟原虫血红素的形成是关键作用模式，体外细胞血红素分级分析支持了这一点。此外，荧光测定表明在氧化条件下会产生活性氧，这表明存在一条辅助途径有助于化合物的抗疟原虫活性。这些发现突出了基于二茂铁基的分子杂化物作为抗疟药物开发中有望候选物的潜力。
