2-Pyridylquinolone antimalarials with improved antimalarial activity and physicochemical properties

A series of 2-pyridylquinolones has been prepared in 5–7 steps and through lead optimisation, antimalarial activity as low as 12 nM against Plasmodium falciparum ( Pf ) has been achieved. Compared with previous analogues in this series, selected molecules have improved solubility, a reduced potentia...

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Bibliographic Details
Published in:MedChemComm 2015-07, Vol.6 (7), p.1252-1259
Main Authors: Charoensutthivarakul, Sitthivut, David Hong, W., Leung, Suet C., Gibbons, Peter D., Bedingfield, Paul T. P., Nixon, Gemma L., Lawrenson, Alexandre S., Berry, Neil G., Ward, Stephen A., Biagini, Giancarlo A., O'Neill, Paul M.
Format: Article
Language:English
Subjects:
Plasmodium
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Summary:A series of 2-pyridylquinolones has been prepared in 5–7 steps and through lead optimisation, antimalarial activity as low as 12 nM against Plasmodium falciparum ( Pf ) has been achieved. Compared with previous analogues in this series, selected molecules have improved solubility, a reduced potential for off-target toxicity and improved metabolic stability profiles. Docking studies performed with a homology model of the Pfbc 1 complex target demonstrate a key role for the Tyr16 residues in the recognition of highly active quinolone based inhibitors.
ISSN:2040-2503
2040-2511
DOI:10.1039/C5MD00062A