New Benzamides as Multi-Targeted Compounds: A Study on Synthesis, AChE and BACE1 Inhibitory Activity and Molecular...

The synthesis of eleven new and previously undescribed benzamides was designed. These compounds were specifically projected as potential inhibitors of the enzymes acetylcholinesterase (AChE) and β-secretase (BACE1). N,N'-(1,4-phenylene)bis(3-methoxybenzamide) was most active against AChE, with an inhibitory concentration of AChE IC₅₀ = 0.056 µM, while the IC₅₀ for donepezil was 0.046 µM. This compound was also the most active against the BACE1 enzyme. The IC₅₀ value was 9.01 µM compared to that for quercetin, with IC₅₀ = 4.89 µM. Quantitative results identified this derivative to be the most promising. Molecular modeling was performed to elucidate the potential mechanism of action of this compound. Dynamic simulations showed that new ligands only had a limited stabilizing effect on AChE, but all clearly reduced the flexibility of the enzyme. It can, therefore, be concluded that a possible mechanism of inhibition increases the stiffness and decreases the flexibility of the enzyme, which obviously impedes its proper function. An analysis of the H-bonding patterns suggests a different mechanism (from other ligands) when interacting the most active derivative with the enzyme.