Background: Phenolic Mannich bases were 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 were also 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 /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 were evaluated spectrophotometrically
towards AChE and hCA I and II enzymes.
Results: 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.