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

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

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.

Highlights

Malaria is a devastating disease with over 214 million clinical cases in 2015.1 In that year alone, the World HealthOrganization (WHO) estimated 438 000 deaths, mostly among children under five in Sub-Saharan Africa
The favorable potency, selectivity, DMPK properties, and efficacy coupled with a novel mechanism of action, inhibition of translation elongation factor 2 (Pf EF2), led to progression of 2 (DDD107498) to preclinical development
Iterative rounds of drug design, synthesis, and biological evaluation were driven by the Medicines for Malaria Venture (MMV) compound progression criteria.[7]

Summary

Introduction

Malaria is a devastating disease with over 214 million clinical cases in 2015.1 In that year alone, the World Health. Organization (WHO) estimated 438 000 deaths, mostly among children under five in Sub-Saharan Africa. The current malaria control programs that combine preventive measures with artemisinin combination therapy (ACT) treatment have proven very effective in reducing the malaria burden. The number of deaths from malaria has fallen by 4% per year, and between 2000 and 2015 the number of clinical cases of malaria has been estimated to have decreased by 40% where the disease is endemic in Africa.[2] in recent years, parasite resistance to artemisinin has been detected in a Received: May 10, 2016 Published: September 10, 2016.

Methods

Results

Conclusion