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

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

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

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

Beatriz Baragaña et al. J Med Chem. .

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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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Key data for screening hit 1 and preclinical candidate 2. Data reported previously.
Scheme 1
Scheme 1
Conditions: (a) KOH, EtOH/water, 125 °C, microwave, 20 min, 29–58% yield; (b) amine, EDC, HOBt, DMF, room temperature, 16 h, 22–43% yield.
Scheme 2
Scheme 2
Conditions: (a) malonic acid, acetic acid, reflux, 16 h, 54%; (b) SOCl2, DMF, DCM, reflux, 3 h and then 2-pyrrolidin-1-ylethanamine, THF, room temperature, 16 h, 27–43% yield; (c) amine, acetonitrile, 170 °C, microwave, 1 h, 7–54% yield; (d) boronic acid or ester, potassium phosphate, Pd(PPh3)4, DMF/water 3/1, 130 °C, microwave, 30 min, 19–73%.
Scheme 3
Scheme 3
Conditions: (a) morpholine, Et3N, DCM, 16 h, 72% yield; (b) MeMgBr, toluene, reflux, 4 h and then a 10% aqueous HCl, reflux, 1 h, 70% yield; (c) NBS, benzoyl peroxide, dichlorobenzene, 140 °C, 16 h, 70% yield; (d) morpholine, K2CO3, acetonitrile, 40 °C, 16 h, 64% yield; (e) 5-fluoroisatin, KOH, EtOH, 120 °C, microwave, 20 min, 30–76% yield; (f) amine, CDMT, N-methylmorpholine, DCM, 20–61% yield.
Figure 2
Figure 2
Mean blood concentration time profile of compounds 2 and 41 following intravenous or oral administration to male Sprague Dawley rats.
See this image and copyright information in PMC

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