Synthesis and characterization of thymol-derived phenoxy acetamide derivatives using DFT, molecular docking, and parasitological investigations

Abstract

Novel phenoxy acetamide derivatives based on a thymol moiety were synthesized for target parasitological investigation. The newly synthesized compounds, 5a , 5b , 7a , 7b , and 9 , were synthesized as phenoxy acetamide derivatives containing a phthalimide or naphthalimide ring through a condensation reaction with various acid anhydrides. Their structures were confirmed based on spectral data derived through Fourier-transform infrared, proton and carbon-13 nuclear magnetic resonance, and elemental analyses. The parasitological, biochemical, and immunological activities of the compounds were measured. The screened compounds were subjected to molecular docking in the active site of CpCDPK1, in addition to analyses based on Lipinski’s rule and SwissADME. The results showed that compounds 5a , 5b , and 7b demonstrated promising antiparasitic activity, characterized by high gastrointestinal absorption and favorable drug-likeness profiles. Furthermore, 5a and 7b exhibited higher binding affinities than that of the reference drug. In practical assessments, compound 7b exhibited the highest percentage reduction in oocyst counts (67%). Density functional theory calculations were performed to assess the thermodynamic stability, molecular geometry, frontier molecular orbital energy gaps, and molecular electrostatic potentials of compounds 5a , 5b , 7a , 7b , and 9 .