Generation of quinolone antimalarials targeting the Plasmodium falciparum mitochondrial respiratory chain for the treatment and prophylaxis of malaria
Language: 
English
Abstract: 

There is an urgent need for new antimalarial drugs with novel mechanisms of action to deliver effective control and eradication programs. Parasite resistance to all existing antimalarial classes, including the artemisinins, has been reported during their clinical use. A failure to generate new antimalarials with novel mechanisms of action that circumvent the current resistance challenges will contribute to a resurgence in the disease which would represent a global health emergency. Here we present a unique generation of quinolone lead antimalarials with a dual mechanism of action against two respiratory enzymes, NADH:ubiquinone oxidoreductase (Plasmodium falciparum NDH2) and cytochrome bc(1). Inhibitor specificity for the two enzymes can be controlled subtly by manipulation of the privileged quinolone core at the 2 or 3 position. Inhibitors display potent (nanomolar) activity against both parasite enzymes and against multidrug-resistant P. falciparum parasites as evidenced by rapid and selective depolarization of the parasite mitochondrial membrane potential, leading to a disruption of pyrimidine metabolism and parasite death. Several analogs also display activity against liver-stage parasites (Plasmodium cynomolgi) as well as transmission-blocking properties. Lead optimized molecules also display potent oral antimalarial activity in the Plasmodium berghei mouse malaria model associated with favorable pharmacokinetic features that are aligned with a single-dose treatment. The ease and low cost of synthesis of these inhibitors fulfill the target product profile for the generation of a potent, safe, and inexpensive drug with the potential for eventual clinical deployment in the control and eradication of falciparum malaria.

Author(s): 
Biagini, Giancarlo A.
Fisher, Nicholas
Shone, Alison E.
Mubaraki, Murad A.
Srivastava, Abhishek
Hill, Alisdair
Antoine, Thomas
Warman, Ashley J.
Davies, Jill
Pidathala, Chandrakala
Amewu, Richard K.
Leung, Suet C.
Sharma, Raman
Gibbons, Peter
Hong, David W.
Pacorel, Bénédicte
Lawrenson, Alexandre S.
Charoensutthivarakul, Sitthivut
Taylor, Lee
Berger, Olivier
Mbekeani, Alison
Stocks, Paul A.
Nixon, Gemma L.
Chadwick, James
Hemingway, Janet
Delves, Michael J.
Sinden, Robert E.
Zeeman, Anne-Marie
Kocken, Clemens H. M.
Berry, Neil G.
O'Neill, Paul M.
Ward, Stephen A.
Item Type: 
Journal Article
Publication Title: 
Proceedings of the National Academy of Sciences of the United States of America
Journal Abbreviation: 
Proc. Natl. Acad. Sci. U.S.A.
Publication Date: 
5/22/2012
Publication Year: 
2012
Pages: 
8298-8303
Volume: 
109
Issue: 
21
ISSN: 
1091-6490
DOI: 
10.1073/pnas.1205651109
Library Catalog: 
PubMed
Extra: 
PMID: 22566611 PMCID: PMC3361392

Turabian/Chicago Citation

Giancarlo A. Biagini, Nicholas Fisher, Alison E. Shone, Murad A. Mubaraki, Abhishek Srivastava, Alisdair Hill, Thomas Antoine, Ashley J. Warman, Jill Davies, Chandrakala Pidathala, Richard K. Amewu, Suet C. Leung, Raman Sharma, Peter Gibbons, David W. Hong, Bénédicte Pacorel, Alexandre S. Lawrenson, Sitthivut Charoensutthivarakul, Lee Taylor, Olivier Berger, Alison Mbekeani, Paul A. Stocks, Gemma L. Nixon, James Chadwick, Janet Hemingway, Michael J. Delves, Robert E. Sinden, Anne-Marie Zeeman, Clemens H. M. Kocken, Neil G. Berry, Paul M. O'Neill and Stephen A. Ward. 5/22/2012. "Generation of quinolone antimalarials targeting the Plasmodium falciparum mitochondrial respiratory chain for the treatment and prophylaxis of malaria." Proceedings of the National Academy of Sciences of the United States of America 109: 21: 8298-8303. 10.1073/pnas.1205651109.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1073/pnas.1205651109 | issn = 1091-6490 | volume = 109 | pages = 8298-8303 | last = Biagini | first = Giancarlo A. | coauthors = Fisher, Nicholas, Shone, Alison E., Mubaraki, Murad A., Srivastava, Abhishek, Hill, Alisdair, Antoine, Thomas, Warman, Ashley J., Davies, Jill, Pidathala, Chandrakala, Amewu, Richard K., Leung, Suet C., Sharma, Raman, Gibbons, Peter, Hong, David W., Pacorel, Bénédicte, Lawrenson, Alexandre S., Charoensutthivarakul, Sitthivut, Taylor, Lee, Berger, Olivier, Mbekeani, Alison, Stocks, Paul A., Nixon, Gemma L., Chadwick, James, Hemingway, Janet, Delves, Michael J., Sinden, Robert E., Zeeman, Anne-Marie, Kocken, Clemens H. M., Berry, Neil G., O'Neill, Paul M., Ward, Stephen A. | title = Generation of quinolone antimalarials targeting the Plasmodium falciparum mitochondrial respiratory chain for the treatment and prophylaxis of malaria | journal = Proceedings of the National Academy of Sciences of the United States of America | date = 5/22/2012 | pmid = | pmc = }} </ref>