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
- 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
DOIAbstract
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 inhibitio...