Biological evaluation, molecular docking and DFT calculations of pyrrole-based derivatives as dual acting AChE/MAO-B inhibitors

<p>Considering the complex pathophysiology of Alzheimer's disease (AD), the multitarget ligand strategy is expected to provide superior effects for the treatment of the neurological disease compared to the classic single target strategy. Thus, six pyrrole-based compounds were evaluated for their dual monoamine oxidase type B (MAO-B) and acetylcholinesterase (AChE) inhibitory capacities. Most of the compounds revealed good AChE activities at 10 µM concentrations. 5d most potently inhibited AChE with 75%, while the hydrazide 5 demonstrated blocking effect of 51% at 10 µM concentrations. However, limited MAO-B inhibitory effects were observed with the exception of compounds 3, and especially 5 (30% inhibition at 1 µM). The in vitro assessments showed that the unsubstituted pyrrole-based hydrazide 5 is the best dual inhibitor of MAO-B/AChE enzymes. Subsequent in silico molecular docking simulations of 5 in the active sites of MAO-B (2V5Z) and AChE (4EY6) displayed the formation of stable enzyme-ligand complexes. To rationalize the biological assays, density functional theory (DFT) calculations were carried out at the B3LYP/6-311<sup>++</sup>(d,p) level of theory. Overall, the results demonstrated that the pyrrole-based hydrazide 5 is a dual-acting AchE/MAO-B inhibitor with good antioxidant properties, which could be considered as a candidate for future lead-optimizations.</p&gt