2-Pyridylquinolone        antimalarials with improved antimalarial activity and physicochemical properties

Sitthivut Charoensutthivarakul; W. David Hong; Suet C. Leung; Peter D. Gibbons; Paul T. P. Bedingfield; Gemma L. Nixon; Alexandre S. Lawrenson; Neil G. Berry; Stephen A. Ward; Giancarlo A. Biagini; Paul M. O'Neill

doi:10.1039/C5MD00062A

2-Pyridylquinoloneantimalarials with improved antimalarial activity and physicochemical properties†

Sitthivut Charoensutthivarakul,^a W. David Hong,^a Suet C. Leung,^a Peter D. Gibbons,^a Paul T. P. Bedingfield,^b Gemma L. Nixon,^a Alexandre S. Lawrenson,^a Neil G. Berry,^a Stephen A. Ward,^b Giancarlo A. Biagini^b and Paul M. O'Neill*^a

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^a Department of Chemistry, University of Liverpool, Liverpool, UK
E-mail: pmoneill@liverpool.ac.uk

^b Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, UK

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.

MedChemComm

2-Pyridylquinoloneantimalarials with improved antimalarial activity and physicochemical properties†

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2-Pyridylquinolone antimalarials with improved antimalarial activity and physicochemical properties

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