Imidazole Derivatives as Promising Agents for the Treatment of Chagas Disease

Abstract

More than 100 years after being first described, Chagas disease remains endemic in 21 Latin American countries and has spread to other continents. Indeed, this disease, which is caused by the protozoan parasite Trypanosoma cruzi, is no longer just a problem for the American continents but has become a global health threat. Current therapies, i.e., nifurtimox and benznidazole (Bz), are far from being adequate, due to their undesirable effects and their lack of efficacy in the chronic phases of the disease. In this work, we present an in-depth phenotypic evaluation in T. cruzi of a new class of imidazole compounds, which were discovered in a previous phenotypic screen against different trypanosomatids and were designed as potential inhibitors of cAMP phosphodiesterases (PDEs). The confirmation of several activities similar or superior to that of Bz prompted a synthesis program of hit optimization and extended structure-activity relationship aimed at improving drug-like properties such as aqueous solubility, which resulted in additional hits with 50% inhibitory concentration (IC 50 ) values similar to that of Bz. The cellular effects of one representative hit, compound 9, on bloodstream trypomastigotes were further investigated. Transmission electron microscopy revealed cellular changes, after just 2 h of incubation with the IC 50 concentration, that were consistent with induced autophagy and osmotic stress, mechanisms previously linked to cAMP signaling. Compound 9 induced highly significant increases in both cellular and medium cAMP levels, confirming that inhibition of T. cruzi PDE(s) is part of its mechanism of action. The potent and selective activity of this imidazole-based PDE inhibitor class against T. cruzi constitutes a successful repurposing of research into inhibitors of mammalian PDEs.

Screening of a PDE-focused library identifies imidazoles with in vitro and in vivo antischistosomal activity

“…These imidazoles are structurally related to a family of human PDE10A inhibitors and have also shown phenotypic activities in trypanosomatids (Sebastián-Pérez et al, 2018; de Araújo et al, 2019). Further developments will focus on additional SAR, on validating the SmPDEs (particularly of the PDE10 family) as the targets for these compounds, on transcriptomics to explain the observed sex differences in drug susceptibility, and on pharmacokinetic studies to rationally improve dosage regimens.…”

Discovery of NovelSchistosoma MansoniPDE4A Inhibitors as Potential Agents against Schistosomiasis

“…In this work, the search for new drugs to treat schistosomiasis was based on a targetbased approach with the aim to discover inhibitors of a cyclic nucleotide phosphodiesterase from S. mansoni (SmPDE), which has been recently proposed as a potential anti-Schistosoma target [15]. Phosphodiesterase (PDE) inhibitors have similarly been proposed as antiparasitic agents for a range of protozoan infections such as sleeping sickness [16], leishmaniasis [17], Chagas disease [18], giardiasis [19] or apicomplexan infections [20] because of the role of increased levels of cAMP caused by inhibition of the corresponding PDE [21]. Less is known about the cyclicnucleotid signalling in helminths although it was reported the characterization of key proteins from this pathway in schistosomes [22,23] and also the vital role of cAMPdependent protein kinase A in adult S. mansoni motor activity [24].…”

Efficacy of Novel Pyrazolone Phosphodiesterase Inhibitors in Experimental Mouse Models of Trypanosoma cruzi

“…The rounding of parasites induced by NPD-227 suggests an impact on the osmoregulation system, already described as an outcome of PDEC inhibition in T. cruzi (9). Indeed, we have previously shown that exposure to other classes of PDE inhibitors, specifically imidazoles (25) and phthalazinones (26), causes profound ultrastructural damage in the Golgi, flagellar pocket, and plasma membrane of T. cruzi. These observations are suggestive of osmotic stress and may be related to increased levels of cAMP.…”