Evaluation of Chalcone (E)‑3-(4-Fluorophenyl)-1-(2-hydroxy-3,4,6-trimethoxyphenyl)-prop-2-en-1-one against Trypanosoma cruzi (Y Strain): In Vitro Assay, In Silico Drug-Target Analysis, and MPO-Based Drug Likeness.

Authors

José Ivo Lima Pinto Filho, Francisco Nithael Melo Lucio, Lyanna Rodrigues Ribeiro, Matheus Nunes da Rocha, Hélcio Silva Dos Santos, Francisco Wagner de Queiroz Almeida-Neto, Emanuel Paula Magalhaes, Alice Maria Costa Martins, Ramon Róseo Paula Pessoa Bezerra de Menezes, Márcia Machado Marinho, Pedro De Lima-Neto, Emmanuel Silva Marinho

Published in

ACS omega. Volume 11. Issue 30. Pages 44583-44613. Aug 04, 2026. Epub Jul 23, 2026.

Abstract

Chagas disease (CD), once found mainly in underdeveloped countries, is becoming a public health problem in the developed world. Although the drug benznidazole (BZN) is effective in the acute phase of the disease, it causes toxicity due to the formation of reactive substances resulting from presystemic metabolism, which have the ability to bind to DNA structures. This study conducts experimental tests with the epimastigote and trypomastigote species of the parasite, followed by drug-target interaction analyses through molecular docking against the enzymes trypanothione reductase, cruzain, and TcGAPDH, as well as pharmacokinetic prediction based on MPO analyses. In vitro tests revealed CPN4F's significant efficacy in reducing host cell viability and inhibiting parasite growth. Molecular docking indicated CPN4F's favorable energy ordering and superiority to BZN against the cruzain target (ΔG < -6.0 kcal mol^-1), while molecular dynamics simulations showed that the complex remains stable in the 500 ns range. Pharmacokinetic estimates suggested high cell permeability (P _app > 10 × 10^-6 cm/s) but potential metabolic stability concerns (CL_int,u > 8 mL/min/kg), showing good oral bioavailability, although with moderate metabolism. The CPN4F molecule demonstrates potent in vitro efficacy against Chagas disease, outperforming BZN in molecular docking studies targeting cruzain. Despite concerns about metabolic stability due to its high cell permeability and lipophilic nature, CPN4F exhibits low acute oral toxicity, highlighting its potential as a safe and effective treatment option.

PMID:
42568956
Bibliographic data and abstract were imported from PubMed on 08 Aug 2026.

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