Abstract
Current treatment of Chagas disease (CD) is based on two substances, nifurtimox (NT) and benzonidazole (BZ), both considered unsatisfactory mainly due to their low activities and high toxicity profile. One of the main challenges faced in CD management concerns the identification of new drugs active in the acute and chronic phases and with good pharmacokinetic profiles. In this work, we studied the bioactivity of twenty 2-(1H-pyrazol-1-yl)-1,3,4-thiadiazole derivatives against Trypanosoma cruzi epimastigotes and trypomastigotes. We identified seven derivatives with promising activity against epimastigote forms with IC50 values ranging from 6 µM to 44 µM. Most of the compounds showed no significant toxicity against murine macrophages. Our initial investigation on the mechanism of action indicates that this series of compounds may exert their anti-parasitic effect, inducing cell membrane damage. The results in trypomastigotes showed that one derivative, PDAN 78, satisfactorily inhibited metabolic alteration at all concentrations. Moreover, we used molecular modeling to understand how tridimensional and structural aspects might influence the observed bioactivities. Finally, we also used in silico approaches to assess the potential pharmacokinetic and toxicological properties of the most active compounds. Our initial results indicate that this molecular scaffold might be a valuable prototype for novel and safe trypanocidal compounds.
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The fellowships granted by CNPq (316568/2021–0 and 163130/2013–2), CAPES (Financial Code 001) and FAPERJ (E-26/203.246/2017, E-26/200.982/2021, E-26/010.000984/2019, E-26/210.002/2020, and E-26/201.369/2021) are gratefully acknowledged.
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These authors did the biological experimets—AFMF, CSFP, RMSG, GPT, DHJ, RXF
These authors did the substance sinthesis—DTGG, NB
This author did the in-silico assay—MLB, NLVR
These authors wrote the paper—AFMF, CSFP, GPT, RMSG, PAFP, GPT, DHJ, RXF
These authors revised the experiments- PAFP, KC, NB, RXF
These authors revised the manuscript- GPT, PAFP, KC, NB, RXF
These authors revised plainned the experiments—KC, NB, RXF
These authors revised received the funds—NB, RXF
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Natalia Lidmar von Ranke performed the in silico analyzes of this work and contributed as lead author.
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Faria, A.F.M., de Souza Ferreira Pereira, C., Teixeira, G.P. et al. In vitro evaluation of 2-(1H-pyrazol-1-yl)-1,3,4-thiadiazole derivatives against replicative and infective stages of Trypanosoma cruzi. J Bioenerg Biomembr 55, 409–421 (2023). https://doi.org/10.1007/s10863-023-09982-7
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DOI: https://doi.org/10.1007/s10863-023-09982-7