Structural Optimization and Biological Activity of Pyrazole Derivatives: Virtual Computational Analysis, Recovery Assay and 3D Culture Model as Potential Predictive Tools of Effectiveness against Trypanosoma cruzi.

Lorraine Martins Rocha Orlando,Leonardo Da Silva Lara,Byanca Silva Ferreira,Cynthia Nathalia Pereira,Rafaela Corrêa Silva,Guilherme Curty Lechuga,Maurício Silva Dos Santos,Mirian Claudia S Pereira

doi:10.3390/molecules26216742

Lorraine Martins Rocha Orlando, Leonardo Da Silva Lara + Show 6 more

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https://doi.org/10.3390/molecules26216742

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Abstract

Chagas disease, a chronic and silent disease caused by Trypanosoma cruzi, is currently a global public health problem. The treatment of this neglected disease relies on benznidazole and nifurtimox, two nitroheterocyclic drugs that show limited efficacy and severe side effects. The failure of potential drug candidates in Chagas disease clinical trials highlighted the urgent need to identify new effective chemical entities and more predictive tools to improve translational success in the drug development pipeline. In this study, we designed a small library of pyrazole derivatives (44 analogs) based on a hit compound, previously identified as a T. cruzi cysteine protease inhibitor. The in vitro phenotypic screening revealed compounds 3g, 3j, and 3m as promising candidates, with IC50 values of 6.09 ± 0.52, 2.75 ± 0.62, and 3.58 ± 0.25 µM, respectively, against intracellular amastigotes. All pyrazole derivatives have good oral bioavailability prediction. The structure–activity relationship (SAR) analysis revealed increased potency of 1-aryl-1H-pyrazole-imidazoline derivatives with the Br, Cl, and methyl substituents in the para-position. The 3m compound stands out for its trypanocidal efficacy in 3D microtissue, which mimics tissue microarchitecture and physiology, and abolishment of parasite recrudescence in vitro. Our findings encourage the progression of the promising candidate for preclinical in vivo studies.

Highlights

Chagas disease, caused by the protozoan Trypanosoma cruzi, is among the 20 neglected tropical diseases combated by the World Health Organization [1]
This study focused on the optimization of hit compounds, 5-amino-1-aryl-4-(4,5dihydro-1H-imidazol-2-yl)-1H-pyrazole, previously identified by the group [13], capable of binding cruzipain and partially inhibiting (>50%) the cysteine protease activity of T. cruzi
The phenotypic screening demonstrated that, in general, the synthesized pyrazole derivatives have low activity against trypomastigotes (IC50 > 34 μM), but three pyrazole-imidazoline analogs (3g, 3j, and 3m) showed activity against intracellular amastigotes similar to Bz (IC50 = 4.67 ± 0.22 μM), reaching IC50 values between 2.75 and 6.09 μM and high selectivity index (SI > 40)

Summary

Introduction

Chagas disease, caused by the protozoan Trypanosoma cruzi, is among the 20 neglected tropical diseases combated by the World Health Organization [1]. This century-old disease, known as American trypanosomiasis, remains endemic in 21 countries in Latin America but has become globalized due to the migratory flow of infected individuals to different continents [2]. The chronic phase is mostly asymptomatic (indeterminate form) in 60–70% of cases This silent disease may progress to cardiomyopathy (30–40%) as well as digestive (megacolon and megaesophagus; 10%) and neurological (10%) manifestations [4,5,6]. Heart failure and sudden death, caused by the damage of the heart muscle and its nervous system, are important outcomes of chronic Chagas cardiomyopathy (CCC)

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