Design of anti-parasitic and anti-fungal hydroxy-naphthoquinones that are less susceptible to drug resistance.
|
| Abstract |
Atovaquone is a hydroxy-naphthoquinone that is used to treat parasitic and fungal infections including Plasmodium falciparum (malaria), Pneumocystis jivorecii (pneumonia) and Toxoplasma gondii (toxoplasmosis). It blocks mitochondrial oxidation of ubiquinol in these organisms by binding to the ubiquinol oxidation site of the cytochrome bc(1) complex. Failure of atovaquone treatment has been linked to the appearance of mutations in the mitochondrially encoded gene for cytochrome b. In order to determine the optimal parameters required for inhibition of respiration in parasites and pathogenic fungi and overcome drug resistance, we have synthesized and tested the inhibitory activity of novel hydroxy-naphthoquinones against blood stage P. falciparum and liver stage P. berghei and against cytochrome bc(1) complexes isolated from yeast strains bearing mutations in cytochrome b associated with resistance in Plasmodium, Pneumocystis, and Toxoplasma. One of the new inhibitors is highly effective against an atovaquone resistant Plasmodium and illustrates the type of modification to the hydroxy-naphthoquinone ring of atovaquone that might mitigate drug resistance.
|
|---|---|
| Authors | Louise M Hughes, Charlotte A Lanteri, Michael T O'Neil, Jacob D Johnson, Gordon W Gribble, Bernard L Trumpower |
| Journal | Molecular and biochemical parasitology (Mol Biochem Parasitol) Vol. 177 Issue 1 Pg. 12-9 (May 2011) ISSN: 1872-9428 [Electronic] Netherlands |
| PMID | 21251932 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.) |
| Copyright | Copyright © 2011 Elsevier B.V. All rights reserved. |
| Chemical References |
|
| Topics |
|
Join CureHunter, for free Research Interface BASIC access!
Realize the full power of the drug-disease research graph!