Antimalarial Lead-Optimization Studies on a 2,6-Imidazopyridine Series within a Constrained Chemical Space To
Claire Le Manach1, Tanya Paquet1, Kathryn Wicht1
1Drug Discovery and Development Center (H3D), Department of Chemistry , University of Cape Town , Rondebosch 7701 , South Africa.
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.
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