| Summary: | Chagas disease, a chronic and silent disease caused by <i>Trypanosoma cruzi</i>, 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 <i>T. cruzi</i> cysteine protease inhibitor. The in vitro phenotypic screening revealed compounds <b>3g</b>, <b>3j</b>, and <b>3m</b> as promising candidates, with IC<sub>50</sub> 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-1<i>H</i>-pyrazole-imidazoline derivatives with the Br, Cl, and methyl substituents in the <i>para</i>-position. The <b>3m</b> 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.
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