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ChemMedChem. 2015 Jan;10(1):47-51. doi: 10.1002/cmdc.201402362. Epub 2014 Oct 14.

Drug delivery to the malaria parasite using an arterolane-like scaffold.

Author information

1
Department of Pharmaceutical Chemistry, University of California, San Francisco, 1700 4th Street, San Francisco, CA 94158 (USA).

Abstract

Antimalarial agents artemisinin and arterolane act via initial reduction of a peroxide bond in a process likely mediated by ferrous iron sources in the parasite. Here, we report the synthesis and antiplasmodial activity of arterolane-like 1,2,4-trioxolanes specifically designed to release a tethered drug species within the malaria parasite. Compared with our earlier drug delivery scaffolds, these new arterolane-inspired systems are of significantly decreased molecular weight and possess superior metabolic stability. We describe an efficient, concise and scalable synthesis of the new systems, and demonstrate the use of the aminonucleoside antibiotic puromycin as a chemo/biomarker to validate successful drug release in live Plasmodium falciparum parasites. Together, the improved drug-like properties, more efficient synthesis, and proof of concept using puromycin, suggests these new molecules as improved vehicles for targeted drug delivery to the malaria parasite.

KEYWORDS:

Plasmodium falciparum; antimalarial agents; drug delivery; puromycin; targeted prodrugs; trioxolanes

PMID:
25314098
PMCID:
PMC4420023
DOI:
10.1002/cmdc.201402362
[Indexed for MEDLINE]
Free PMC Article

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