Acetylcholinesterase and Carbonic Anhydrase Inhibition Profiles of New 5-HMF Chalcones and Their Ester Derivatives

Acetylcholinesterase (AChE) is one of the most important therapeutic targets in the treatment of neurological disorders such as Alzheimer's disease. In recent years, studies on the use of carbonic anhydrase (CA) inhibitors in the treatment of Alzheimer's disease have attracted considerable attention. In this study, novel benzene/5-HMF-chalcone hybrids and their benzoate esters were synthesized. Furthermore, the AChE, carbonic anhydrases I and II (CA I and II) inhibition potentials of the compounds were evaluated through in vitro enzyme inhibition assays and molecular docking studies to identify new potential drug candidate molecules. According to the inhibition results, the Ki values of the synthesized compounds were found to be in the range of 1.51–2.91 nM against AChE, 26.15–68.66 nM against CA I, and 27.91–107.04 nM against CA II. Molecular docking studies revealed that the compounds bind to both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE, with Glide scores ranging from –5.76 to –8.50 kcal/mol. In contrast, the molecules interacted with the active site of CA I/II by coordinating with the catalytic Zn2+ ion. All compounds complied with Lipinski's Rule of Five, indicating favorable drug-like properties. These results suggest that 5-HMF-chalcone hybrids and their benzoate derivatives could serve as promising scaffolds for the development of new anti-Alzheimer's agents. These findings suggest that 5-HMF-chalcone hybrids and their benzoate derivatives may be useful in establishing the structural basis of new anti-Alzheimer's agents.