Protozoan Parasite Growth Inhibitors Discovered by Cross-Screening Yield Potent Scaffolds for Lead Discovery

Tropical protozoal infections are
a significant cause of morbidity
and mortality worldwide; four in particular (human African trypanosomiasis
(HAT), Chagas disease, cutaneous leishmaniasis, and malaria) have
an estimated combined burden of over 87 million disability-adjusted
life years. New drugs are needed for each of these diseases. Building
on the previous identification of NEU-617 (1) as a potent
and nontoxic inhibitor of proliferation for the HAT pathogen (Trypanosoma brucei), we have now tested this class of analogs
against other protozoal species: T. cruzi (Chagas
disease), Leishmania major (cutaneous leishmaniasis),
and Plasmodium falciparum (malaria). Based on hits
identified in this screening campaign, we describe the preparation
of several replacements for the quinazoline scaffold and report these
inhibitors’ biological activities against these parasites.
In doing this, we have identified several potent proliferation inhibitors
for each pathogen, such as 4-((3-chloro-4-((3-fluorobenzyl)­oxy)­phenyl)­amino)-6-(4-((4-methyl-1,4-diazepan-1-yl)­sulfonyl)­phenyl)­quinoline-3-carbonitrile
(NEU-924, 83) for T. cruzi and N-(3-chloro-4-((3-fluorobenzyl)­oxy)­phenyl)-7-(4-((4-methyl-1,4-diazepan-1-yl)­sulfonyl)­phenyl)­cinnolin-4-amine
(NEU-1017, 68) for L. major and P. falciparum.