Design, synthesis and in vitro evaluation of novel water-soluble prodrugs of buparvaquone.

Abstract

Novel water-soluble phosphate prodrugs (2b-5b) of buparvaquone-oxime (1a) and buparvaquone-O-methyloxime (1b) were synthesized and evaluated in vitro as potential oral prodrugs against leishmaniasis. Buparvaquone-oxime (1a), and most probably also buparvaquone-O-methyloxime (1b), released the parent buparvaquone via a cytochrome P450-catalysed reaction. The prodrugs 2b-5b showed significantly higher aqueous solubilities (>4 mg/ml) than buparvaquone (< or = 0.03 microg/ml) over a pH range of 3.0-7.4. The prodrugs 2b, 3b and 5b rapidly released (t1/2 = 7 min) the corresponding oximes of buparvaquone (1a and 1b), and prodrug 4b at a moderate rate (t1/2 = 22.5 min) in alkaline phosphatase solution in vitro. Prodrug 3b was the most chemically stable in the aqueous solutions over a pH range of 3.0-7.4 (t1/2 > 8 days). Although buparvaquone-oxime (1a) has been shown to undergo a cytochrome P450-catalysed oxidation in liver microsomes to the parent buparvaquone and behave as a novel bioreversible prodrug, its usefulness is limited in oral drug delivery due to its poor aqueous solubility, like buparvaquone itself. Further phosphorylation of an oxime form of buparvaquone significantly increased water solubility, and this novel approach is therefore useful to improve physicochemical properties of drugs containing a ketone functional group.

• Authors: Antti Mäntylä, Jarkko Rautio, Tapio Nevalainen, Pekka Keski-Rahkonen, Jouko Vepsälainen, Tomi Järvinen
• Journal: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences (Eur J Pharm Sci) Vol. 23 Issue 2 Pg. 151-8 (Oct 2004) ISSN: 0928-0987 [Print] Netherlands
• PMID: 15451003 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiprotozoal Agents
• Buffers
• Indicators and Reagents
• Lipids
• Naphthoquinones
• Prodrugs
• buparvaquone
• Alkaline Phosphatase

Topics

• Alkaline Phosphatase (chemistry)
• Antiprotozoal Agents (chemical synthesis, pharmacology)
• Buffers
• Drug Design
• Hydrolysis
• Indicators and Reagents
• Lipids (chemistry)
• Magnetic Resonance Spectroscopy
• Naphthoquinones (chemical synthesis, pharmacology)
• Prodrugs (chemical synthesis, pharmacology)
• Solubility