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

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 (CLint,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.