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dc.contributor.authorParkinson, Christopher J.
dc.contributor.authorHaynes, Richard K.
dc.contributor.authorBirrell, Geoffrey W.
dc.contributor.authorChavchich, Marina
dc.contributor.authorMackenzie, Donna
dc.date.accessioned2019-09-02T08:06:07Z
dc.date.available2019-09-02T08:06:07Z
dc.date.issued2019
dc.identifier.citationParkinson, C.J. et al. 2019. Development of pyridyl thiosemicarbazones as highly potent agents for the treatment of malaria after oral administration. Journal of antimicrobial chemotherapy, 74(10):2965-2973. [https://doi.org/10.1093/jac/dkz290]en_US
dc.identifier.issn0305-7453
dc.identifier.issn1460-2091 (Online)
dc.identifier.urihttp://hdl.handle.net/10394/33267
dc.identifier.urihttps://academic.oup.com/jac/advance-article/doi/10.1093/jac/dkz290/5536337?searchresult=1
dc.identifier.urihttps://doi.org/10.1093/jac/dkz290
dc.description.abstractObjectives Drug resistance exists to all current and investigational antimalarial drug classes. Consequently, we have set out to develop chemically and mechanistically discrete antimalarials. Here we report on the development of thiosemicarbazone (TSC) antimalarials, with TSC3 as the most advanced lead. Methods Thiosemicarbazones were generated through simple condensation reactions of thiosemicarbazides and ketones. TSC3 was selected and tested for in vitro antimalarial activities against MDR Plasmodium falciparum lines using the [3H]hypoxanthine growth assay, in vitro cytotoxicity against mammalian cell lines using the alamarBlue fluorescence cell viability assay, in vivo potency in the mouse–Plasmodium berghei model and blood exposure in mice measured by LC-MS for pharmacokinetic analysis. Results TSC3 showed potent in vitro activity against atovaquone-, dihydroartemisinin-, chloroquine- and mefloquine-resistant P. falciparum lines (EC50 <15 nM). The selectivity index (EC50 cells/EC50Pf W2 line) of TSC3 was >500 in two of three mammalian cell lines. In P. berghei-infected mice, TSC3 showed potent activity in the Peters 4 day suppression test (ED50 1.2 mg/kg/day) and was as potent as artesunate and chloroquine in the curative modified Thompson test. A single oral dose of TSC3 at 16 mg/kg in healthy mice achieved a mean maximum blood concentration of 1883 ng/mL at 1 h after dosing and an elimination half-life of 48.7 h in groups of five mice. Conclusions TSC3 shows promise as a persistent, potent and orally effective antimalarial. This, coupled with the extremely low cost of synthesis, suggests that the further development of antimalarial thiosemicarbazones is clearly warranteden_US
dc.language.isoenen_US
dc.publisherOxford Univ Pressen_US
dc.subjectChloroquineen_US
dc.subjectAntimalarialsen_US
dc.subjectCell linesen_US
dc.subjectMalariaen_US
dc.subjectMammalsen_US
dc.subjectPlasmodium falciparumen_US
dc.subjectThiosemicarbazonesen_US
dc.subjectMiceen_US
dc.subjectArtesunateen_US
dc.subjectCytotoxicityen_US
dc.subjectThompson's testen_US
dc.titleDevelopment of pyridyl thiosemicarbazones as highly potent agents for the treatment of malaria after oral administrationen_US
dc.typeArticleen_US
dc.contributor.researchID22966390 - Haynes, Richard Kingston


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