Chagas disease is caused by the intracellular protozoan parasite Trypanosomal cruzi, and current drugs are lacking in terms of desired safety and efficacy profiles. Following on a recently reported high-throughput screening campaign, we have explored initial structure-activity relationships around a class of imidazole-based compounds. This profiling has uncovered compounds 4c (NEU321) and 4j (NEU704), which are potent against in vitro cultures of T. cruzi and are greater than 160-fold selective over host cells. We report in vitro drug metabolism and properties profiling of 4c and show that this chemotype inhibits the T cruzi CYP51 enzyme, an observation confirmed by X-ray crystallographic analysis. We compare the binding orientation of 4c to that of other, previously reported inhibitors. We show that 4c displays a significantly better ligand efficiency and a shorter synthetic route over previously disclosed CYP51 inhibitors, and should therefore be considered a promising lead compound for further optimization.
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.
Hesperadin, an established human Aurora B inhibitor, was tested against cultures of Trypanosoma brucei, Leishmania major, and Plasmodium falciparum, and was identified to be a potent proliferation inhibitor. A series of analogs was designed and tested to establish the initial structure-activity relationships for each parasite. In this study, we identified multiple non-toxic compounds with high potency against T. brucei and P. falciparum with good selectivity. These compounds may represent an opportunity for continued optimization.
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