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

Journal of Medicinal Chemistry
Suet LeungPaul M O'Neill

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.

References

Aug 20, 1976·Science·W Trager, J B Jensen
Jan 5, 2002·Trends in Parasitology·R W SnowK Marsh
Nov 26, 2002·Journal of Chemical Information and Computer Sciences·Joseph L DurantJames G Nourse
Apr 16, 2004·The Journal of Clinical Investigation·Nicholas J White
Apr 24, 2004·Antimicrobial Agents and Chemotherapy·Martin SmilksteinMichael Riscoe
Apr 6, 2005·Journal of Chemical Information and Modeling·Kejun LiuS Stanley Young
Apr 28, 2006·Antimicrobial Agents and Chemotherapy·Giancarlo A BiaginiStephen A Ward
Nov 30, 2006·Drug Discovery Today·Peter Willett
May 15, 2007·Trends in Parasitology·Nicholas FisherGiancarlo A Biagini
Mar 6, 2008·Molecular Pharmacology·Giancarlo A BiaginiStephen A Ward
Apr 10, 2008·Journal of Medicinal Chemistry·Clive L YeatesMaría L León
Dec 9, 2009·Journal of Medicinal Chemistry·Hamish S SutherlandAndrew M Thompson
Apr 30, 2010·Journal of Chemical Information and Modeling·David Rogers, Mathew Hahn
Feb 2, 2011·PLoS Medicine·UNKNOWN malERA Consultative Group on Integration Strategies
Feb 12, 2011·PLoS Medicine·UNKNOWN malERA Consultative Group on Drugs
Mar 16, 2011·Current Topics in Medicinal Chemistry·Jeremy N BurrowsTimothy N C Wells

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Citations

Jan 10, 2014·Parasitology·P A StocksP M O'Neill
Sep 2, 2014·Malaria Journal·Richard M BeteckDavid D N'Da
Nov 2, 2013·Future Medicinal Chemistry·Françoise Nepveu, Francesco Turrini
Feb 9, 2016·European Journal of Medicinal Chemistry·Soraya AlnabulsiSally Freeman
Apr 5, 2016·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Abdul NaeemKhalid Khan
Jan 21, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Karène UrginElisabeth Davioud-Charvet
May 4, 2013·Chemical Communications : Chem Comm·Jian-Ping Lin, Ya-Qiu Long
Sep 17, 2019·European Journal of Medicinal Chemistry·Anudeep K NarulaLalit M Nainwal
Apr 14, 2021·Chemistry : a European Journal·Quentin RonzonBastien Nay
Apr 22, 2015·The Journal of Organic Chemistry·Makthala RaviPrem P Yadav
Nov 6, 2020·Journal of Medicinal Chemistry·Chee Wei AngMark A T Blaskovich
Dec 28, 2019·Journal of the American Chemical Society·Yoshio NakataniLars J C Jeuken

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Methods Mentioned

BETA
X-ray
column chromatography

Software Mentioned

GSKs pyridone bc
Grafit

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