Dataset Information

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

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.

SUBMITTER: Baragana B

PROVIDER: S-EPMC5108032 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Baragaña Beatriz B Norcross Neil R NR Wilson Caroline C Porzelle Achim A Hallyburton Irene I Grimaldi Raffaella R Osuna-Cabello Maria M Norval Suzanne S Riley Jennifer J Stojanovski Laste L Simeons Frederick R C FR Wyatt Paul G PG Delves Michael J MJ Meister Stephan S Duffy Sandra S Avery Vicky M VM Winzeler Elizabeth A EA Sinden Robert E RE Wittlin Sergio S Frearson Julie A JA Gray David W DW Fairlamb Alan H AH Waterson David D Campbell Simon F SF Willis Paul P Read Kevin D KD Gilbert Ian H IH

Journal of medicinal chemistry 20160910 21

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, EC<sub>50</sub> = 120 nM) was optimized to lead molecules with low nanomolar in vitro potency. Improvement of the pharmacokinetic profile led to sev ...[more]

PMID: 27631715

Similar Datasets

Project description:BackgroundThe parasitic trematode Schistosoma mansoni is one of the major causative agents of human schistosomiasis, which afflicts 200 million people worldwide. Praziquantel remains the main drug used for schistosomiasis treatment, and reliance on the single therapy has been prompting the search for new therapeutic compounds against this disease. Our group has demonstrated that heme crystallization into hemozoin (Hz) within the S. mansoni gut is a major heme detoxification route with lipid droplets involved in this process and acting as a potential chemotherapeutical target. In the present work, we investigated the effects of three antimalarial compounds, quinine (QN), quinidine (QND) and quinacrine (QCR) in a murine schistosomiasis model by using a combination of biochemical, cell biology and molecular biology approaches.Methodology/principal findingsTreatment of S. mansoni-infected female Swiss mice with daily intraperitoneal injections of QN, and QND (75 mg/kg/day) from the 11(th) to 17(th) day after infection caused significant decreases in worm burden (39%-61%) and egg production (42%-98%). Hz formation was significantly inhibited (40%-65%) in female worms recovered from QN- and QND-treated mice and correlated with reduction in the female worm burden. We also observed that QN treatment promoted remarkable ultrastructural changes in male and female worms, particularly in the gut epithelium and reduced the granulomatous reaction to parasite eggs trapped in the liver. Microarray gene expression analysis indicated that QN treatment increased the expression of transcripts related to musculature, protein synthesis and repair mechanisms.ConclusionsThe overall significant reduction in several disease burden parameters by the antimalarial quinoline methanols indicates that interference with Hz formation in S. mansoni represents an important mechanism of schistosomicidal action of these compounds and points out the heme crystallization process as a valid chemotherapeutic target to treat schistosomiasis.

Project description:BackgroundDespite the strides made in recent decades, the resistance observed in existing antimalarial drugs, and the intricate life cycle of the Plasmodium parasite underscore the pressing need to develop novel and effective therapeutic interventions. This article provides a comprehensive evaluation of the outcomes stemming from screening a library comprising 48 compounds (TCAMS) against Plasmodium falciparum.MethodsThis study focused on characterizing the IC50 values of compounds from the Tres Cantos Antimalarial Set (TCAMS) library via a double-labelling method of P. falciparum parasites with SYBR Green-I and MitoTracker Deep Red, which were evaluated via flow cytometry. Evaluation of the cytotoxicity of the best candidates in human embryonic kidney (HEK293) cells, chemoinformatic analysis, and exploration of the effects of the compounds on the action of serotonin and melatonin in the erythrocytic life cycle of the parasite.ResultsIC50 characterization confirmed that 93.75% of the compounds tested exhibited antimalarial activity at concentrations below 2 micromolar (µM), with 5 compounds showing IC50 values below 50 nM (nM) (15.21 ± 5.97 nM to 45.82 ± 5.11 nM). Furthermore, 12 compounds presented IC50 values between 50 and 100 nM (57.43 ± 12.25 nM to 100.6 ± 22.89 nM), highlighting their potent in vitro efficacy against P. falciparum. Cytotoxicity evaluation in HEK293 cells revealed that 12 from 17 compounds did not significantly reduce cell viability. Cheminformatics analysis clustered the compounds based on structural and physicochemical similarities, revealing distinct structural patterns. Exploration of hypothetical targets from the TCAMS library identified 27 compounds with potential targets, 15 specifically targeted serotonergic receptors. Subsequent serotonin and melatonin treatment experiments indicated that certain compounds could inhibit both effects on parasitaemia, suggesting a complex interaction with signaling in P. falciparum.ConclusionsThis study identifies promising antimalarial candidates with low IC50 values and highlights the significance of targeting serotonin receptors in the development of potential antimalarial drugs.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets