Design, synthesis, and characterization of novel aminoalcohol quinolines with strong in vitro antimalarial activity

Malaria is the fifth most lethal parasitic infections in the world. Herein, five new series of aminoalcohol quinolines including fifty-two compounds were designed, synthesized and evaluated in vitro against Pf3D7 and PfW2 strains. Among them, fourteen displayed IC50 values below or near of 50.0 nM w...

Full description

Saved in:
Bibliographic Details
Published in:European journal of medicinal chemistry 2022-01, Vol.228, p.113981-113981, Article 113981
Main Authors: Dassonville-Klimpt, A., Schneider, J., Damiani, C., Tisnerat, C., Cohen, A., Azas, N., Marchivie, M., Guillon, J., Mullié, C., Agnamey, P., Totet, Anne, Dormoi, J., Taudon, N., Pradines, B., Sonnet, P.
Format: Article
Language:English
Subjects:
Amino Alcohols - chemical synthesis
Amino Alcohols - chemistry
Amino Alcohols - pharmacology
Aminoalcohol quinolines
Animals
Antimalarial drug resistance
Antimalarials - chemical synthesis
Antimalarials - chemistry
Antimalarials - pharmacology
Cell Line
Chemical Sciences
Cricetulus
Dose-Response Relationship, Drug
Drug Design
Ether-A-Go-Go Potassium Channels - antagonists & inhibitors
Ether-A-Go-Go Potassium Channels - metabolism
Female
Humans
in vitro
In vivo
Malaria
Malaria - drug therapy
Material chemistry
Mefloquine analogs
Mice
Mice, Inbred BALB C
Microsomes, Liver - chemistry
Microsomes, Liver - metabolism
Molecular Structure
P. falciparum
Parasitic Sensitivity Tests
Plasmodium falciparum - drug effects
Quinolines - chemical synthesis
Quinolines - chemistry
Quinolines - pharmacology
Structure-Activity Relationship
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Malaria is the fifth most lethal parasitic infections in the world. Herein, five new series of aminoalcohol quinolines including fifty-two compounds were designed, synthesized and evaluated in vitro against Pf3D7 and PfW2 strains. Among them, fourteen displayed IC50 values below or near of 50.0 nM whatever the strain with selectivity index often superior to 100.17b was found as a promising antimalarial candidate with IC50 values of 14.9 nM and 11.0 nM against respectively Pf3D7 and PfW2 and a selectivity index higher than 770 whatever the cell line is. Further experiments were achieved to confirm the safety and to establish the preliminary ADMET profile of compound 17b before the in vivo study performed on a mouse model of P. berghei ANKA infection. The overall data of this study allowed to establish new structure-activity relationships and the development of novel agents with improved pharmacokinetic properties. [Display omitted] •Compounds synthetized with good yields and excellent enantiomeric excesses.•Fourteen antimalarial hits with IC50 values close to 50 nM on both Pf3D7 and PfW2.•Hits with strong selectivity index higher than 100.•Lead 17b possesses good pharmacokinetic profiles.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2021.113981