Multi-Target Analysis of Xanthone Derivatives as Potential Anti-Trypanosoma cruzi Agents: An Integrated Computational Screening

Abstract

Chagas disease, caused by the parasite Trypanosoma cruzi, affects approximately 8 million people worldwide. The search for new therapeutic candidates is intensified by the limited efficacy and severe adverse effects of current treatments, such as benznidazole and nifurtimox. In this context, integrated computational strategies encompassing structural, dynamic, and pharmacokinetic filters act complementarily to guide the rational screening of promising compounds. Here, eight xanthone derivatives were evaluated using integrated in silico approaches, including multiparametric analyses of physicochemical, pharmacokinetic, toxicological, molecular docking, and conformational stability properties. Pharmacokinetic predictions indicated high human intestinal absorption (> 90%), apparent permeability consistent with efficient transcellular diffusion (Papp > 1.0 × 10⁻⁵ cm/s), and TPSA values below 90 Ų, suggesting favorable oral bioavailability. Among the compounds, XN1 and XN5 emerged as promising candidates, showing multi-parameter optimization (MPO) scores of 5, molecular weights below 400 g/mol, and advantageous absorption and permeability profiles. Although XN5 exhibited higher lipophilicity and associated toxicity alerts, both compounds demonstrated promising pharmacokinetic features. Molecular docking analyses revealed that XN5 presented superior binding affinity for TcReductase and TcGAPDH, outperforming co-crystallized ligands and suggesting stable protein-ligand complexes. Pharmacophoric mapping confirmed the conservation of key molecular recognition features, corroborating the stereoelectronic complementarity of xanthone derivatives with the active sites. conformational stability simulations further indicated that XN5 exhibited the most stable behavior with TcReductase and a performance comparable to BZN and chalepin with TcGAPDH. In conclusion, in silico results highlight XN5 as a promising candidate for Chagas disease treatment.