title: A carbamate-based approach to primaquine prodrugs: antimalarial activity, chemical stability and enzymatic activation.
abstract: O-Alkyl and O-aryl carbamate derivatives of the antimalarial drug primaquine were synthesised as potential prodrugs that prevent oxidative deamination to the inactive metabolite carboxyprimaquine. Both O-alkyl and O-aryl carbamates undergo hydrolysis in alkaline and pH 7.4 phosphate buffers to the parent drug, with O-aryl carbamates being ca. 10(6)-10(10) more reactive than their O-alkyl counterparts. In human plasma O-alkyl carbamates were stable, whereas in contrast their O-aryl counterparts rapidly released the corresponding phenol product, with primaquine being released only slowly over longer incubation periods. Activation of the O-aryl carbamates in human plasma appears to be catalysed by butyrylcholinesterase (BuChE), which leads to carbamoylation of the catalytic serine of the enzyme followed by subsequent slow enzyme reactivation and release of parent drug. Most of the O-aryl and O-alkyl carbamates are activated in rat liver homogenates with half-lives ranging from 9 to 15 h, while the 4-nitrophenyl carbamate was hydrolysed too rapidly to determine an accurate rate constant. Antimalarial activity was studied using a model consisting of Plasmodium berghei, Balb C mice and Anopheles stephensi mosquitoes. When compared to controls, ethyl and n-hexyl carbamates were able to significantly reduce the percentage of infected mosquitos as well as the mean number of oocysts per infected mosquito, thus indicating that O-alkyl carbamates of primaquine have the potential to be developed as transmission-blocking antimalarial agents.
authors.affiliation: Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy,University of Lisbon, Avenida das Forças Armadas, 1649-003 Lisboa, Portugal.
authors.forename: Graça
authors.initials: G
authors.lastname: Mata
authors.forename: Virgílio E
authors.initials: VE
authors.lastname: do Rosário
authors.forename: Jim
authors.initials: J
authors.lastname: Iley
authors.forename: Luís
authors.initials: L
authors.lastname: Constantino
authors.forename: Rui
authors.initials: R
authors.lastname: Moreira
mesh_terms: D000818:Animals; D000852:Anopheles / Q000187:drug effects*; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002091:Butyrylcholinesterase / Q000378:metabolism; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D004355:Drug Stability; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006868:Hydrolysis; D008099:Liver / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010962:Plasmodium berghei / Q000187:drug effects; D011319:Primaquine / Q000031:analogs & derivatives*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats
chemical_list: D000962:Antimalarials; D002219:Carbamates; D011355:Prodrugs; D002091:Butyrylcholinesterase; D011319:Primaquine