title: Drug delivery to the malaria parasite using an arterolane-like scaffold.
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.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, 1700 4th Street, San Francisco, CA 94158 (USA).
authors.forename: Shaun D
authors.initials: SD
authors.lastname: Fontaine
authors.forename: Benjamin
authors.initials: B
authors.lastname: Spangler
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.forename: Erica M W
authors.initials: EM
authors.lastname: Lauterwasser
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.forename: Adam R
authors.initials: AR
authors.lastname: Renslo
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry*; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007700:Kinetics; D008862:Microsomes, Liver / Q000378:metabolism; D010545:Peroxides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000378:metabolism; D015800:Protozoan Proteins / Q000737:chemistry / Q000378:metabolism; D011691:Puromycin / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D004337:Drug Carriers; D006573:Heterocyclic Compounds, 1-Ring; D010545:Peroxides; D015800:Protozoan Proteins; D013141:Spiro Compounds; C489136:arterolane; D011691:Puromycin
keywords: Plasmodium falciparum; antimalarial agents; drug delivery; puromycin; targeted prodrugs; trioxolanes