Pyridyl Benzamides as a Novel Class of Potent Inhibitors for the Kinetoplastid Trypanosoma brucei

A whole-organism screen of approximately
87000 compounds against Trypanosoma
brucei brucei identified a number of promising compounds
for medicinal chemistry optimization. One of these classes of compounds
we termed the pyridyl benzamides. While the initial hit had an IC50 of 12 μM, it was small enough to be attractive
for further optimization, and we utilized three parallel approaches
to develop the structure–activity relationships. We determined
that the physicochemical properties for this class are generally favorable
with particular positions identified that appear to block metabolism
when substituted and others that modulate solubility. Our most active
compound is 79, which has an IC50 of 0.045
μM against the human pathogenic strain Trypanosoma
brucei rhodesiense and is more than 4000 times less
active against the mammalian L6 cell line.