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 (IC₅₀) 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 IC₅₀ 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.

Keywords: Chagas disease; drug discovery; imidazole.

FIG 1

Synthesis of substituted N-(thiazole-2-yl)urea derivatives (compounds 13 to 17) and N-(1H-imidazol-2-yl)urea derivatives (compounds 18 to 23) using isocyanates. MW, microwave.

FIG 2

Synthesis of substituted N-(1H-imidazol-2-yl)urea derivatives (compounds 24 to 38) using CDI. rt, room temperature.

FIG 3

Transmission electron microscopy of Y strain BTs that were untreated (A) or treated with compound 9 for 2 h (B to K). The treated parasites exhibited important features that included flagellar pocket dilation (B, hash mark), disruption of the Golgi apparatus (C, asterisk), and extensive blebs (E and G, angle brackets) and shedding events (J, double asterisks) in the plasma membrane, as well as a large number of myelin figures (K) and membranous profiles surrounding cytoplasmic organelles (D and H) and complete disorganization of cytoplasmic structures (I).

FIG 4

Intracellular (A) and extracellular (B) cAMP levels after incubation of BTs with compound 9 or positive controls (NPD-001 and NPD-008). All bars represent the mean and standard error of the mean of three independent experiments, each conducted in duplicate. P values were calculated using Student t test: *, P < 0.05; **, P < 0.01; ***, P < 0.001.