Synthesis, vibrational analysis, thermal analysis, quantum-chemical calculation, molecular docking and dynamics, DMPK and evaluation of the antichagasic potential of a fluorinated chalcone

Abstract

Chagas disease affects 7 million people worldwide and is endemic in 20 Latin American countries. It is estimated to cause about 14,000 deaths annually and more than 75 million people are at risk of infection. Therefore, there is an urgent need for the development of new therapeutic agents. In this study, we describe the synthesis, characterization, and tripanocidal activity of the chalcone (E)-1-(4-aminophenyl)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)prop‑2-en-1-one (DF). The compound was characterized by spectroscopic techniques and its potential against T. cruzi was evaluated by in vitro assays against Y strain forms and in silico analyses including quantum analyses, multiparameter optimization (MPO) based pharmacokinetic prediction and molecular docking and dynamics simulations. The results of the present study show that DF has a trypanocidal effect, presents a significant reduction in toxicity compared to benznidazole, and can induce morphological changes such as cellular extravasation and the presence of pores, observed by scanning electron microscopy in addition to flow cytometry data, highlighted by staining with 7-AAD, indicative of necrosis, with better selectivity than benznidazole. Molecular docking results showed that the chalcone ligand has a higher affinity for the cruzain enzyme, calculated as -7.5 kcal/mol, forming a stable complex interacting at the benznidazole site. The pharmacokinetic study showed that chalcone has the properties of lipophilicity and polarity that favor its passive permeability (Papp), estimated in 2.1 × 10−5 cm/s in intestinal cells. These results are relevant because chalcone has been described as a molecule with the potential to inhibit growth or cause death of T. cruzi.