Molecular Docking Studies and Biological Activities of Chalcones Targeting Acetylcholinesterase, and Carbonic Anhydrase Isoenzymes

Chalcone molecules are important pharmacophores in medicinal chemistry and have various biological functions, including inhibitory effects on the enzymes carbonic anhydrase (CA) and acetylcholinesterase (AChE). Carbonic anhydrase I and II inhibitors are used in the treatment of disorders such as retinal and cerebral edema (CAI), epilepsy, and glaucoma (CA II). Furthermore, acetylcholinesterase inhibitors, which were originally created to treat Alzheimer's disease, have proven useful for patients suffering from Parkinson's disease-related memory problems, behavioral disorders, and cognitive decline. The drugs on the market have adverse effects. Therefore, new drug candidates are required to address the issues raised. In this study, chalcone compounds were synthesized to investigate their CA and AChE inhibitory effects and their chemical structures were confirmed using NMR. The inhibitory effects of the synthesized compounds on carbonic anhydrase and acetylcholine esterase enzymes were presented for the first time in this study. Carbonic anhydrases and AChE inhibitory effects of 1-21 were investigated using described methodologies. As a result of the studies, it was determined that the compounds were in the inhibition range of 2.65-82.33 µM for hCA I and 2.63-74.89 µM for hCA II, while the IC50 values of the reference AZA were 46.75 µM (hCA I) and 38.25 µM (hCA II). Moreover, these compounds inhibited AChE in the range of 15.53-177.46, while the IC50 value of the reference drug Tacrin was measured as 25.78 nM. Among the synthesized chalcone derivatives, compound 5 emerged as the most potent inhibitor for hCA I and AChE, while compound 13 was the strongest for hCA II. AutoDock Vina docking results showed that compound 5 had the strongest affinity for hCA I (-8.0 kcal mol⁻¹) and AChE (-7.0 kcal mol⁻¹), while compound 13 was most potent for hCA II (-8.1 kcal mol⁻¹). Key interactions with catalytic residues suggest that halogen and methoxy groups enhance enzyme binding, stability, and hydrogen bonding. These findings suggest that these compounds hold promise as potential drug candidates for CA and AChE related disorders.