Discovery of a quinoline-4-carboxamide derivative with a novel mechanism of action, multistage antimalarial activity, and potent in vivo efficacy

Baragaña, Beatriz and Norcross, Neil R. and Wilson, Caroline and Porzelle, Achim and Hallyburton, Irene and Grimaldi, Raffaella and Osuna-Cabello, Maria and Norval, Suzanne and Riley, Jennifer and Stojanovski, Laste and Simeons, Frederick R. C. and Wyatt, Paul G. and Delves, Michael J. and Meister, Stephan and Duffy, Sandra and Avery, Vicky M. and Winzeler, Elizabeth A. and Sinden, Robert E. and Wittlin, Sergio and Frearson, Julie A. and Gray, David W. and Fairlamb, Alan H. and Waterson, David and Campbell, Simon F. and Willis, Paul and Read, Kevin D. and Gilbert, Ian H.. (2016) Discovery of a quinoline-4-carboxamide derivative with a novel mechanism of action, multistage antimalarial activity, and potent in vivo efficacy. Journal of medicinal chemistry, 59 (21). pp. 9672-9685.

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Abstract

The antiplasmodial activity, DMPK properties, and efficacy of a series of quinoline-4-carboxamides are described. This series was identified from a phenotypic screen against the blood stage of Plasmodium falciparum (3D7) and displayed moderate potency but with suboptimal physicochemical properties and poor microsomal stability. The screening hit (1, EC50 = 120 nM) was optimized to lead molecules with low nanomolar in vitro potency. Improvement of the pharmacokinetic profile led to several compounds showing excellent oral efficacy in the P. berghei malaria mouse model with ED90 values below 1 mg/kg when dosed orally for 4 days. The favorable potency, selectivity, DMPK properties, and efficacy coupled with a novel mechanism of action, inhibition of translation elongation factor 2 (PfEF2), led to progression of 2 (DDD107498) to preclinical development.

Faculties and Departments:	09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
UniBasel Contributors:	Wittlin, Sergio
Item Type:	Article, refereed
Article Subtype:	Research Article
Publisher:	American Chemical Society
ISSN:	0022-2623
Note:	Publication type according to Uni Basel Research Database: Journal article
Language:	English
Identification Number:	doi: 10.1021/acs.jmedchem.6b00723 pmid: 27631715
edoc DOI:	10.5451/unibas-ep54411
Last Modified:	20 Oct 2017 06:09
Deposited On:	20 Apr 2017 13:18

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