Synthesis and antileishmanial activity of novel buparvaquone oxime derivatives.

Abstract

Novel oxime derivatives (2, 3 and 5) of buparvaquone (1) and O-methyl-buparvaquone (4) were synthesized and their in vitro activities against Leishmania donovani, the causative agent of visceral leishmaniasis (VL), were determined. Buparvaquone-oxime (2) was also studied as a bioreversible prodrug structure of buparvaquone (1). Buparvaquone-oxime (2) released buparvaquone (1) in vitro when it was incubated with induced rat liver microsomes, which suggests that the oxime-structure is a useful prodrug template for developing novel prodrugs of buparvaquone and other hydroxynaphthoquinones. Moreover, the formation of NO(2)(-) , formed via oxidation of NO, was confirmed during the bioconversion. The release of NO from buparvaquone-oxime (2) may provide an additional therapeutic effect in the treatment of leishmaniasis. Buparvaquone-oxime (2) and buparvaquone-O-methyloxime (3) demonstrated moderate activity against amastigotes of the Leishmania species that causes VL. However, the studied oximes (2, 3) most probably did not release buparvaquone (1) and NO during the present in vitro experiment. Further in vivo studies are needed to verify the biological activity of buparvaquone-oximes in the treatment of leishmaniasis.

• Authors: Antti Mäntylä, Jarkko Rautio, Tapio Nevalainen, Jouko Vepsälainen, Risto Juvonen, Howard Kendrick, Tracy Garnier, Simon L Croft, Tomi Järvinen
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 12 Issue 13 Pg. 3497-502 (Jul 01 2004) ISSN: 0968-0896 [Print] England
• PMID: 15186834 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiprotozoal Agents
• Naphthoquinones
• Oximes
• buparvaquone oxime
• buparvaquone

Topics

• Animals
• Antiprotozoal Agents (chemical synthesis, chemistry, pharmacology)
• Leishmania donovani (drug effects)
• Leishmaniasis, Visceral (drug therapy, parasitology)
• Macrophages (drug effects, parasitology)
• Magnetic Resonance Spectroscopy
• Microsomes, Liver (drug effects, enzymology)
• Molecular Structure
• Naphthoquinones (chemical synthesis, chemistry, pharmacology)
• Oximes (chemical synthesis, chemistry, pharmacology)
• Rats
• Rats, Wistar