Furanocarboxamide Derivative Against Congenital Toxoplasmosis: Synthesis, Bioactivity, ADME Profile and in silico Insights

Abstract

Congenital toxoplasmosis remains a significant therapeutic challenge within the spectrum of Toxoplasma gondii infections is estimated about 190,000 cases per year, with a considerable infection rate worldwide (ca. 29%). This study describes the synthesis and pharmacological evaluation of compound 1, a furanocarboxamide derivative. Compound 1 was synthesized through a four-step route with a 64% global yield. To mimic congenital infection, the compound was evaluated against Toxoplasma gondii in placental cells, demonstrating a half maximal inhibitory concentration (IC50) of 2.91 ± 0.12 mM. Given the phylogenetic proximity within the Apicomplexa phylum, compound 1 was also tested against chloroquine-resistant Plasmodium falciparum, showing potent activity (IC50 of 2.04 ± 1.37 µM). Conversely, evaluation against Trypanosoma cruzi revealed low potency (IC50 of 44.12 ± 0.79 µM) suggesting a more specific profile for apicomplexan parasites. ADME (adsorption distribution metabolism, excretion, and toxicity) profiling indicated high permeability but highlighted pharmacokinetic challenges, including high lipophilicity, low aqueous solubility, and low metabolic stability. To explore the mechanism of action, a computational study was conducted using molecular docking against twenty-six essential Toxoplasma gondii enzymes. Molecular dynamics (MD) simulations of the top eight candidates identified TgCDPK1, PKA, and the cytochrome bc1 complex as the most promising targets. Overall, this work establishes compound 1 as a promising hit for congenital toxoplasmosis and malaria, providing a clear roadmap for future hit-to-lead optimization to overcome its current pharmacokinetic limitations.