Aminoalkylated Phenolic Chalcones: Investigation of Biological Effects on Acetylcholinesterase and Carbonic Anhydrase I and II as Potential Lead Enzyme Inhibitors

Background: Phenolic Mannich bases have been reported as acetylcholinesterase (AChE) inhibitors for the medication of Alzheimer's disease. Carbonic Anhydrases (CAs) are molecular targets for anticonvulsant, diuretic and antiglaucoma drugs in the clinic. Phenolic compounds have also been mentioned as CA inhibitors. The importance of Mannich bases in drug design inspired our research group to design novel phenolic Mannic bases as potent enzyme inhibitors. Objective: In this study, novel Mannich bases, 1-(3,5-bis-aminomethyl-4-hydroxyphenyl)-3-(4- substitutedphenyl)-2-propen-1-ones (1-9), were designed to discover new and potent AChE inhibitors for the treatment of Alzheimer's disease and also to report their carbonic anhydrase inhibitory potency against the most studied hCA I and hCA II isoenzymes with the hope to find out promising enzyme inhibitors. Methods: Mannich bases were synthesized by the Mannich reaction. The structures of the compounds were elucidated by 1H NMR, 13C NMR, and HRMS. Enzyme inhibitory potency of the compounds was evaluated spectrophotometrically towards AChE, hCA I and hCA II enzymes. Results and Discussion: The compounds showed inhibition potency in nanomolar concentrations against AChE with Ki values ranging from 20.44±3.17 nM to 43.25±6.28 nM. They also showed CAs inhibition potency with Ki values in the range of 11.76±1.29-31.09±2.7 nM (hCA I) and 6.08 ± 1.18-23.12±4.26 nM (hCA II). Compounds 1 (hCA I), 5 (hCA II), and 4 (AChE) showed significant inhibitory potency against the enzymes targeted. Conclusion: Enzyme assays showed that Mannich derivatives might be considered as lead enzyme inhibitors to design more selective and potent compounds targeting enzyme-based diseases.