| Literature DB >> 30256636 |
Claire Le Manach1, Tanya Paquet1, Kathryn Wicht1, Aloysius T Nchinda1, Christel Brunschwig2, Mathew Njoroge2, Liezl Gibhard2, Dale Taylor2, Nina Lawrence2, Sergio Wittlin3,4, Charles J Eyermann1, Gregory S Basarab1, James Duffy5, Paul V Fish6,7, Leslie J Street1, Kelly Chibale1,8.
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.Entities:
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Year: 2018 PMID： 30256636 DOI： 10.1021/acs.jmedchem.8b01333
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446