Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, 46556, USA.
Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, 46556, USA.
Biometals. 2023 Apr;36(2):315-320. doi: 10.1007/s10534-022-00375-8. Epub 2022 Mar 1.
Despite advances in chemotherapeutic interventions for the treatment of malaria, there is a continuing need for the development of new antimalarial agents. Previous studies indicated that co-administration of chloroquine with antioxidants such as the iron chelator deferoxamine (DFO) prevented the development of persistent cognitive damage in surrogate models of cerebral malaria. The work described herein reports the syntheses and antimalarial activities of covalent conjugates of both natural (siderophores) and artificial iron chelators, namely DFO, ferricrocin and ICL-670, with antimalarial 1,2,4-trioxolanes (ozonides). All of the synthesized conjugates had potent antimalarial activities against the in vitro cultures of drug resistant and drug sensitive strains of Plasmodium falciparum. The work described herein provides the basis for future development of covalent combination of iron chelators and antimalarial chemotherapeutic agents for the treatment of cerebral malaria.
尽管在疟疾的化学治疗干预方面取得了进展，但仍需要开发新的抗疟药物。先前的研究表明，将氯喹与抗氧化剂（如铁螯合剂去铁胺（DFO））联合使用，可以预防脑型疟疾替代模型中持续性认知损伤的发生。本文所述的工作报告了天然（铁载体）和人工铁螯合剂（即 DFO、三价铁血晶素和 ICL-670）与抗疟 1,2,4-三恶烷（臭氧化物）的共价缀合物的合成和抗疟活性。所有合成的缀合物对体外培养的耐药和敏感株疟原虫均具有很强的抗疟活性。本文所述的工作为未来开发铁螯合剂和抗疟化学治疗药物的共价结合物治疗脑型疟疾提供了基础。
