Synthesis, biological evaluation, molecular docking, molecular dynamics, and ADME studies of novel thiouracil derivatives as dual inhibitors of butyrylcholinesterase and acetylcholinesterase enzymes

For the past few decades, there has been an urgent need to discover newer and more effective treatments for Alzheimer's disease due to the increasing prevalence of this neurodegenerative disorder and the limited efficacy of current therapeutic options. In this study, uracil derivatives with diverse substituents at positions 2 and 5 were synthesized and then thionated to produce thiouracil compounds, which were subsequently treated with various amines to yield novel pyrimidine derivatives. The chemical structures of these derivatives were characterized using various spectroscopic techniques (Mass, 1H NMR, and 13C NMR). Evaluation of their effects on butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) showed that most compounds exhibited inhibitory activity. The most active compounds, 12 and 18, demonstrated IC50 values of 0.12 mu M for BChE and 0.39 nM for AChE, respectively. In silico ADME studies assessed the pharmacokinetic properties of these compounds. Molecular dynamics simulations indicated that Compound 12 with BChE and Compound 18 with AChE formed stable interactions, reinforcing their potential as strong inhibitors. These results suggest that the hybrid compounds, particularly Compounds 12 and 18 could be promising candidates for the treatment of Alzheimer's disease.