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

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.