Visceral leishmaniasis is a severe parasitic disease that is one of the most neglected tropical diseases. Treatment options are limited, and there is an urgent need for new therapeutic agents. Following an HTS campaign and hit optimization, a novel series of amino-pyrazole ureas has been identified with potent in vitro antileishmanial activity. Furthermore, compound 26 shows high levels of in vivo efficacy (>90%) against Leishmania infantum, thus demonstrating proof of concept for this series.
Ligand-based similarity screening of proprietary pharmaceutical company libraries enables rapid hit to lead investigation of a chemotype with anti-leishmania activity.
Probing multiple proprietary pharmaceutical libraries
in parallel
via virtual screening allowed rapid expansion of the structure–activity
relationship (SAR) around hit compounds with moderate efficacy against Trypanosoma cruzi, the causative agent of Chagas
Disease. A potency-improving scaffold hop, followed by elaboration
of the SAR via design guided by the output of the phenotypic virtual
screening efforts, identified two promising hit compounds 54 and 85, which were profiled further in pharmacokinetic
studies and in an in vivo model of T. cruzi infection. Compound 85 demonstrated
clear reduction of parasitemia in the in vivo setting,
confirming the interest in this series of 2-(pyridin-2-yl)quinazolines
as potential anti-trypanosome treatments.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.