Synthesis, in Vitro Evaluation, and Antileishmanial Activity of Water-Soluble Prodrugs of Buparvaquone

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dc.contributor Aalto-yliopisto fi
dc.contributor Aalto University en Mäntylä, Antti Garnier, Tracy Rautio, Jarkko Nevalainen, Tapio Vepsäläinen, Jouko Koskinen, Ari Croft, Simon L. Järvinen, Tomi 2016-09-23T09:20:42Z 2004
dc.identifier.citation Mäntylä , A , Garnier , T , Rautio , J , Nevalainen , T , Vepsäläinen , J , Koskinen , A , Croft , S L & Järvinen , T 2004 , ' Synthesis, in Vitro Evaluation, and Antileishmanial Activity of Water-Soluble Prodrugs of Buparvaquone ' Journal of Medical Chemistry , no. 47 , pp. 188-195 . DOI: 10.1021/jm030868a en
dc.identifier.other PURE UUID: 0ef7a283-a6be-4cb7-b4d3-5bc5c6b05af5
dc.identifier.other PURE ITEMURL:
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dc.description.abstract Water-soluble phosphate prodrugs of buparvaquone (1), containing a hydroxynaphthoquinone structure, were synthesized and evaluated in vitro for improved topical and oral drug delivery against cutaneous and visceral leishmaniasis. The successfull prodrug synthesis involved a strong base; e.g., sodium hydride. Buparvaquone-3-phosphate (4a) and 3-phosphonooxymethylbuparvaquone (4b) prodrugs possessed significantly higher aqueous solubilities (>3.5 mg/mL) than the parent drug (e0.03 íg/mL) over a pH range of 3.0-7.4. Moreover, 4a and 4b maintained adequate lipophilicity as indicated by distribution coefficients (log D) between 0.5 and 3.0 over this pH range. Both 4a and 4b were also shown to be substrates for alkaline phosphatase in vitro and thus are promising bioreversible prodrugs for the improved topical and oral bioavailability of 1. Buparvaquone and its prodrugs showed nanomolar or lowmicromolar ED50 activity values against species that cause cutaneous leishmaniasis, e.g., L. major, L. amazonensis, L. aethiopica, L. mexicana, and L. panamensis and also L. donovani, which is the causative agent of visceral leishmaniasis. From these results, the human skin permeation of the prodrugs 4a and 4b were studied in vitro. While no buparvaquone permeated across post mortem skin in vitro during 72 h of experiments, both prodrugs 4a and 4b permeated readily through the skin. In addition, 4b easily released the parent drug in human skin homogenate and, therefore, is a promising prodrug candidate to deliver buparvaquone through the skin for the treatment of cutaneous leishmaniasis. en
dc.format.extent 188-195
dc.format.mimetype application/pdf
dc.language.iso en en
dc.relation.ispartofseries Journal of Medical Chemistry en
dc.relation.ispartofseries issue 47 en
dc.rights openAccess en
dc.title Synthesis, in Vitro Evaluation, and Antileishmanial Activity of Water-Soluble Prodrugs of Buparvaquone en
dc.type A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä fi
dc.description.version Peer reviewed en
dc.contributor.department Department of Chemistry en
dc.subject.keyword buparvaquone
dc.subject.keyword organic chemistry
dc.subject.keyword synthesis
dc.subject.keyword water-soluble
dc.identifier.urn URN:NBN:fi:aalto-201609234399
dc.identifier.doi 10.1021/jm030868a
dc.type.version acceptedVersion

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