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Generation of quinolone antimalarials targeting the Plasmodium falciparum mitochondrial respiratory chain for the treatment and prophylaxis of malaria.

Biagini, Giancarlo ORCID: https://orcid.org/0000-0001-6356-6595, Fisher, Nicholas, Shone, Alison, Mubaraki, Murad A., Srivastava, Abhishek, Hill, Alasdair, Antoine, Thomas, Warman, Ashley, 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, Chadwick, James, Hemingway, Janet ORCID: https://orcid.org/0000-0002-3200-7173, Delves, Michael J, Sinden, Robert E, Zeeman, Anne-Marie, Kocken, Clemens H M, Berry, Neil G, O'Neill, Paul M and Ward, Stephen ORCID: https://orcid.org/0000-0003-2331-3192 (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, Vol 109, Issue 21, pp. 8298-303.

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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.

Item Type: Article
Additional Information: This is a open access article that can be viewed at the URL above.
Subjects: QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 256 Antimalarials
QX Parasitology > Protozoa > QX 135 Plasmodia
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 765 Prevention and control
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 770 Therapy
Faculty: Department: Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group
Digital Object Identifer (DOI): https://doi.org/10.1073/pnas.1205651109
Depositing User: Mary Creegan
Date Deposited: 03 Oct 2012 11:28
Last Modified: 17 Jul 2020 10:57
URI: https://archive.lstmed.ac.uk/id/eprint/3049

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