CYP51 is a P450 enzyme involved in
the biosynthesis of the sterol
components of eukaryotic cell membranes. CYP51 inhibitors have been
developed to treat infections caused by fungi, and more recently the
protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease. To specifically optimize
drug candidates for T. cruzi CYP51
(<i>Tc</i>CYP51), we explored the structure–activity
relationship (SAR) of a <i>N</i>-indolyl-oxopyridinyl-4-aminopropanyl-based
scaffold originally identified in a target-based screen. This scaffold
evolved via medicinal chemistry to yield orally bioavailable leads
with potent anti-T. cruzi activity
in vivo. Using an animal model of infection with a transgenic T. cruzi Y luc strain expressing firefly luciferase,
we prioritized the biaryl and <i>N</i>-arylpiperazine analogues
by oral bioavailability and potency. The drug–target complexes
for both scaffold variants were characterized by X-ray structure analysis.
Optimization of both binding mode and pharmacokinetic properties of
these compounds led to potent inhibitors against experimental T. cruzi infection
