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

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

Research output: Contribution to journalArticle

27 Citations (Scopus)
178 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)9672-9685
Number of pages14
JournalJournal of Medicinal Chemistry
Volume59
Issue number21
Early online date10 Sep 2016
DOIs
Publication statusPublished - 10 Nov 2016

Fingerprint Dive into the research topics of 'Discovery of a quinoline-4-carboxamide derivative with a novel mechanism of action, multistage antimalarial activity, and potent in vivo efficacy'. Together they form a unique fingerprint.

  • Projects

    Profiles

    Cite this