Identification, design and biological evaluation of heterocyclic quinolones targeting Plasmodium falciparum type II NADH:quinone oxidoreductase (PfNDH2) |
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Authors: | 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 E Charoensutthivarakul Sitthivut Taylor Lee Berger Olivier Mbekeani Alison Hill Alasdair Fisher Nicholas E Warman Ashley J Biagini Giancarlo A Ward Stephen A O'Neill Paul M |
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Institution: | Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, UK. |
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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. |
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