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Identification, design and biological evaluation of heterocyclic quinolones targeting Plasmodium falciparum type II NADH:quinone oxidoreductase (PfNDH2).

Leung, Suet C, Gibbons, Peter, Amewu, Richard, Nixon, Gemma L, Pidathala, Chandrakala, Hong, W David, Pacorel, Bénédicte, Berry, Neil G, Sharma, Raman, Stocks, Paul A., Srivastava, Abhishek, Shone, Alison, Charoensutthivarakul, Sitthivut, Taylor, Lee, Berger, Olivier, Mbekeani, Alison, Hill, Alasdair, Fisher, Nicholas, Warman, Ashley, Biagini, Giancarlo ORCID: https://orcid.org/0000-0001-6356-6595, Ward, Stephen ORCID: https://orcid.org/0000-0003-2331-3192 and O'Neill, Paul M (2012) 'Identification, design and biological evaluation of heterocyclic quinolones targeting Plasmodium falciparum type II NADH:quinone oxidoreductase (PfNDH2).'. Journal of medicinal chemistry, Vol 55, Issue 5, pp. 1844-1857.

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Abstract

Following a program undertaken to identify hit compounds against NADH:ubiquinone oxidoreductase (PfNDH2), a novel enzyme target within the malaria parasite Plasmodium falciparum, hit to lead optimization led to identification of CK-2-68, a molecule suitable for further development. In order to reduce ClogP and improve solubility of CK-2-68 incorporation of a variety of heterocycles, within the side chain of the quinolone core, was carried out, and this approach led to a lead compound SL-2-25 (8b). 8b has IC(50)s in the nanomolar range versus both the enzyme and whole cell P. falciparum (IC(50) = 15 nM PfNDH2; IC(50) = 54 nM (3D7 strain of P. falciparum) with notable oral activity of ED(50)/ED(90) of 1.87/4.72 mg/kg versus Plasmodium berghei (NS Strain) in a murine model of malaria when formulated as a phosphate salt. Analogues in this series also demonstrate nanomolar activity against the bc(1) complex of P. falciparum providing the potential added benefit of a dual mechanism of action. The potent oral activity of 2-pyridyl quinolones underlines the potential of this template for further lead optimization studies.

Item Type: Article
Subjects: QV Pharmacology > QV 38 Drug action.
QV Pharmacology > Drug Standardization. Pharmacognosy. Medicinal Plants > QV 771 Standardization and evaluation of drugs
QX Parasitology > Protozoa > QX 135 Plasmodia
Faculty: Department: Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group
Digital Object Identifer (DOI): https://doi.org/10.1021/jm201184h
Depositing User: Mary Creegan
Date Deposited: 18 Dec 2012 14:25
Last Modified: 06 Feb 2018 13:05
URI: http://archive.lstmed.ac.uk/id/eprint/3082

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