This investigation involved the design and preparation of two chalcone analogues using both computational and laboratory approaches, evaluating their capacity to suppress lipoxygenase (LOX), an enzyme involved in inflammatory processes. The work builds upon prior studies where various chalcone derivatives were prepared and structurally confirmed. Here, we describe the repeated synthesis of two selected chalcones, emphasizing computational docking analyses, NMR spectroscopic examinations, and molecular dynamics simulations. Structural assignment for each compound was achieved by integrating data from Nuclear Magnetic Resonance (NMR) spectroscopy and Density Functional Theory (DFT) calculations. Additionally, the influence of substituents on the UV-visible absorption profiles of these chalcone analogues was explored. Docking predictions of LOX–chalcone complexes were subjected to molecular dynamics (MD) simulations to assess their binding stability. Following comprehensive in silico evaluation of the LOX–chalcone interactions, detailed atomic-level binding information for each analogue with 15-LOX-1 and 5-LOX was obtained via Saturation Transfer Difference (STD) NMR experiments. The compounds’ selectivity was further evaluated against human 15-LOX-1 and broad lipoxidase enzymatic activity. Computational findings indicate that these chalcones represent potential lead structures for developing therapeutics aimed at lipoxygenase inhibition.
