Synthesis and Bioactivity Studies on AChE Inhibitory Compounds
Project no. 29581 · Status: Kapanmış · 2023
Summary
<p>Acetylcholine is a neurotransmitter that has an important role in learning and cholinergic activity of the peripheral and central nervous systems. Acetylcholine released from the synaptic gap binds to the receptor and provides cholinergic transmission, then hydrolyzed to choline and acetic acid by cholinesterase enzymes. Pathological disorders that occur as a result of low acetylcholine level in our body occur in some diseases. Since there is a deficiency in the amount of acetylcholine in Alzheimer's disease, myasthenia gravis and glaucoma, acetylcholinesterase (AChE) inhibitors are used in the treatment of these diseases in order to increase the decreasing acetylcholine level.</p><p>Alzheimer's disease (AD) emerges as one of the biggest health threats of the twenty-first century, affecting approximately 60% of the elderly population aged 60-65 years, and it is predicted that there will be 152 million Alzheimer's patients by 2050 (Han et al., 2022; Scheltens et al. et al., 2021; Sharma et al., 2023). AD is a disease with a complex multifactorial pathophysiology with decreased cholinergic transmission, amyloid β plaques, hyperphosphorylation of tau proteins, oxidative stress, mitochondrial dysfunction (Sharma et al., 2023).</p><p>AChE has two ligand binding sites, the peripheral anionic domain (PAS) and the catalytic anionic domain (CAS). It has been found that molecules that can interact with both the PAS region and the active site of the enzyme, which have dual site binding properties, inhibit Aβ aggregation as well as inhibit AChE. Both increasing cholinergic transmission and inhibiting Aβ formation can be considered as a more effective way to treat AD. It has also been found in studies that BChE acts as a compensatory agent in decreasing AChE. Therefore, a new strategy has been developed for drug discovery as anti-Alzheimer's agents with multiple activities such as inhibition of AChE and BChE (Anil et al., 2022; Bayraktar, 2019; Burmaoğlu et al., 2022).</p><p>There are central and peripheral acting AChE inhibitors in different chemical structures on the market. AChE inhibitors donepezil, galantamine, rivastigmine are used in the treatment of Alzheimer's disease, while pyridostigmine and neostigmine, which have a quaternary amine structure, are used in the treatment of myasthenia gravis and glaucoma. From the molecular modeling studies, it is known that the quaternary groups interact with the active pocket of the AChE enzyme. Quaternary structures have the potential to make ionic bonds with the enzyme and interact with cation-π.</p><p>Within the scope of the graduation project, a condensation product with a carbonyl structured intermediate was obtained by subjecting acetophenone to pyridine-3-carbaldehyde with Claisen-Schmidt reaction. The structure of the compound was elucidated by spectroscopic methods (IR, 1H NMR spectroscopy). Then, the AChE and BChE inhibitory activity of the compound was determined according to the modified Ellman method. According to the activity results, our compound inhibited AChE with IC50 values of 2.81 μM and BChE enzyme with IC50 values of 0.105 μM. It can be said that our compound exhibits dual inhibitory properties against both AChE and BChE enzymes at a micromolar level.</p>