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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
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.