Evaluation of 3,4-diethoxy substituted thioureas and their thiazole derivatives as potent anti-Alzheimer's agents: Synthesis, DFT, biological activity and molecular modeling investigations

The current research project aims to develop 3, 4-diethoxy substituted thioureas ( 15 -20 ) and thiazoles ( 22 -23, 25 -26 ) analogs as potential anti-Alzheimer's agents. A total of ten derivatives were synthesized and were further characterized with TLC, FTIR, and NMR techniques. In addition, density functional theory (DFT) calculations and molecular modeling were performed to evaluate the electronic properties and anti-Alzheimer's disease potential of the compounds within the active pockets of the targeted enzymes, respectively. During in -vitro testing, it was determined that all analogs exhibited some degree of inhibitory potential, and analogs (15), (16), (19) , and (26) were found to have excellent potency in inhibiting Alzheimer's disease-related enzymes i.e., monoamine oxidaseA, monoamine oxidase-B, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). Analog (15) demonstrated an IC 50 of 1.33 +/- 0.04 mu M for MAO -A; (16) showed an IC 50 of 1.67 +/- 0.06 mu M for MAO -B, (19) represented an IC 50 of 0.31 +/- 0.02 mu M for AChE, and (26) showed an IC 50 of 0.51 +/- 0.01 mu M for BChE. These compounds have shown a comparable potential with the reference compounds i.e., Clorgyline (for MAO -A), Deprenyl (for MAO -B) and donepezil in case of AChE and BChE, respectively. The study also established a structure-activity relationship and determined that the potency of the analogs depends on the nature, position, number, and electron-donating/-withdrawing effects of the phenyl ring substituents. The identified compounds also exhibited strong binding interactions during molecular docking investigations. Moreover, the most potent complexes of respective targets were found stable during molecular dynamics simulation studies. The findings of the current study revealed that new thioureas and thiazoles analogs exhibited a reactive electronic property, which is essential for anti-cholinesterase activity.