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

Research output: Contribution to journalArticleScientificpeer-review

Researchers

  • Antti Mäntylä
  • Tracy Garnier
  • Jarkko Rautio
  • Tapio Nevalainen
  • Jouko Vepsäläinen
  • Ari Koskinen

  • Simon L. Croft
  • Tomi Järvinen

Research units

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.

Details

Original languageEnglish
Pages (from-to)188-195
JournalJOURNAL OF MEDICINAL CHEMISTRY
Issue number47
Publication statusPublished - 2004
MoE publication typeA1 Journal article-refereed

    Research areas

  • buparvaquone, organic chemistry, synthesis, water-soluble

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