1. 2-Pyridylquinolone antimalarials with improved antimalarial activity and physicochemical properties
- Author
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Alexandre S. Lawrenson, Paul M. O'Neill, Sitthivut Charoensutthivarakul, Paul T. P. Bedingfield, Peter Gibbons, Neil G. Berry, Suet C. Leung, W. David Hong, Gemma L. Nixon, Stephen A. Ward, and Giancarlo A. Biagini
- Subjects
Pharmacology ,biology ,Improved solubility ,medicine.drug_class ,Stereochemistry ,Chemistry ,Organic Chemistry ,Pharmaceutical Science ,Plasmodium falciparum ,Metabolic stability ,biology.organism_classification ,Quinolone ,Biochemistry ,wc_750 ,qw_52 ,Docking (molecular) ,qx_135 ,Drug Discovery ,qv_256 ,medicine ,Molecular Medicine ,Homology modeling - Abstract
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 Pfbc1 complex target demonstrate a key role for the Tyr16 residues in the recognition of highly active quinolone based inhibitors.
- Published
- 2015
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