Antimalarial lead-optimization studies on a 2,6-imidazopyridine series within a constrained chemical space to circumvent atypical dose-response curves against multidrug resistant parasite strains
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
 
ID 4487801
Author(s) Le Manach, Claire; Paquet, Tanya; Wicht, Kathryn; Nchinda, Aloysius T.; Brunschwig, Christel; Njoroge, Mathew; Gibhard, Liezl; Taylor, Dale; Lawrence, Nina; Wittlin, Sergio; Eyermann, Charles J.; Basarab, Gregory S.; Duffy, James; Fish, Paul V.; Street, Leslie J.; Chibale, Kelly
Author(s) at UniBasel Wittlin, Sergio
Year 2018
Title Antimalarial lead-optimization studies on a 2,6-imidazopyridine series within a constrained chemical space to circumvent atypical dose-response curves against multidrug resistant parasite strains
Journal Journal of medicinal chemistry
Volume 61
Number 20
Pages / Article-Number 9371-9385
Abstract A lead-optimization program around a 2,6-imidazopyridine scaffold was initiated based on the two early lead compounds, 1 and 2, that were shown to be efficacious in an in vivo humanized Plasmodium falciparum NODscidIL2Rγnull mouse malaria infection model. The observation of atypical dose-response curves when some compounds were tested against multidrug resistant malaria parasite strains guided the optimization process to define a chemical space that led to typical sigmoidal dose-response and complete kill of multidrug resistant parasites. After a structure and property analysis identified such a chemical space, compounds were prepared that displayed suitable activity, ADME, and safety profiles with respect to cytotoxicity and hERG inhibition.
Publisher American Chemical Society
ISSN/ISBN 0022-2623
edoc-URL https://edoc.unibas.ch/66888/
Full Text on edoc No
Digital Object Identifier DOI 10.1021/acs.jmedchem.8b01333
PubMed ID http://www.ncbi.nlm.nih.gov/pubmed/30256636
 
   

MCSS v5.8 PRO. 0.432 sec, queries - 0.000 sec ©Universität Basel  |  Impressum   |    
10/08/2020