Re-evaluating pretomanid analogues for Chagas disease: Hit-to-lead studies reveal both in vitro and in vivo trypanocidal efficacy.

Phenotypic screening of a 900 compound library of antitubercular nitroimidazole derivatives related to pretomanid against the protozoan parasite Trypanosoma cruzi (the causative agent for Chagas disease) identified several structurally diverse hits with an unknown mode of action. Following initial profiling, a first proof-of-concept in vivo study was undertaken, in which once daily oral dosing of a 7-substituted 2-nitroimidazooxazine analogue suppressed blood parasitemia to low or undetectable levels, although sterile cure was not achieved. Limited hit expansion studies alongside counter-screening of new compounds targeted at visceral leishmaniasis laid the foundation for a more in-depth assessment of the best leads, focusing on both drug-like attributes (solubility, metabolic stability and safety) and maximal killing of the parasite in a shorter timeframe.

The effect of reinfection and mixed Trypanosoma cruzi infections on disease progression in mice.

The progression of Chagas disease (CD) varies significantly from host to host and is affected by multiple factors. In particular, mixed strain infections and reinfections have the potential to exacerbate disease progression subsequently affecting clinical management of patients with CD. Consequently, an associated reduction in therapeutic intervention and poor prognosis may occur due to this exacerbated disease state.

Reactivation of Chagas Disease: Implications for Global Health.

Reactivation of Chagas Disease (CD) is a global public health issue. Reactivation of disease can affect the management of CD and its clinical outcome, adding pressure to global health systems because it exacerbates symptoms, leading to misdiagnosis and delays in the administration of correct treatments. Concurrent infections complicate the issue of reactivation, because there are various parasites and disease treatment regimens that are able to influence or suppress the immune system of the host, reactivating disease within infected individuals.

Chagas disease: the challenge of polyparasitism?

The debilitating zoonosis Chagas disease (CD) is caused by infection with the flagellate protozoan Trypanosoma cruzi. One century after its discovery, a curative agent remains elusive. Immune evasion by T.

Selection and optimization of hits from a high-throughput phenotypic screen against Trypanosoma cruzi.

Background: Inhibitors of Trypanosoma cruzi with novel mechanisms of action are urgently required to diversify the current clinical and preclinical pipelines. Increasing the number and diversity of hits available for assessment at the beginning of the discovery process will help to achieve this aim.

Results: We report the evaluation of multiple hits generated from a high-throughput screen to identify inhibitors of T.

Complexes of Trypanosoma cruzi sterol 14α-demethylase (CYP51) with two pyridine-based drug candidates for Chagas disease: structural basis for pathogen selectivity.

Chagas disease, caused by the eukaryotic (protozoan) parasite Trypanosoma cruzi, is an alarming emerging global health problem with no clinical drugs available to treat the chronic stage. Azole inhibitors of sterol 14α-demethylase (CYP51) were proven effective against Chagas, and antifungal drugs posaconazole and ravuconazole have entered clinical trials in Spain, Bolivia, and Argentina. Here we present the x-ray structures of T.