Discovery of a Quinoline-4-carboxamide Derivative with a Novel Mechanism of Action, Multistage Antimalarial Activity, and Potent in Vivo Efficacy

J Med Chem. 2016 Nov 10;59(21):9672-9685. doi: 10.1021/acs.jmedchem.6b00723.

Beatriz Baragaña ¹, Neil R Norcross ¹, Caroline Wilson ¹, Achim Porzelle ¹, Irene Hallyburton ¹, Raffaella Grimaldi ¹, Maria Osuna-Cabello ¹, Suzanne Norval ¹, Jennifer Riley ¹, Laste Stojanovski ¹, Frederick R C Simeons ¹, Paul G Wyatt ¹, Michael J Delves ², Stephan Meister ³, Sandra Duffy ⁴, Vicky M Avery ⁴, Elizabeth A Winzeler ³, Robert E Sinden ², Sergio Wittlin ⁵ ⁶, Julie A Frearson ¹, David W Gray ¹, Alan H Fairlamb ¹, David Waterson ⁷, Simon F Campbell ⁷, Paul Willis ⁷, Kevin D Read ¹, Ian H Gilbert ¹

Affiliations

1 Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
2 Cell and Molecular Biology, Department of Life Sciences, Imperial College , London, SW7 2AZ, U.K.
3 School of Medicine, University of California, San Diego , 9500 Gilman Drive, La Jolla, California 92093, United States.
4 Eskitis Institute, Griffith University , Brisbane Innovation Park, Nathan Campus, Brisbane, QLD 4111, Australia.
5 Swiss Tropical and Public Health Institute, Swiss TPH, Socinstrasse 57, 4051 Basel, Switzerland.
6 University of Basel , CH-4003 Basel, Switzerland.
7 Medicines for Malaria Venture , International Centre Cointrin, Entrance G, 3rd Floor, Route de Pré-Bois 20, P.O. Box 1826, CH-1215, Geneva 15, Switzerland.

PMID: 27631715 DOI: 10.1021/acs.jmedchem.6b00723

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.

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