Studies on Pyridinium Derivatives as Potential Cholinesterase Inhibitors
Project no. 29580 · Status: Kapanmış · 2023
Summary
<p>Alzheimer's disease is a progressive, neurodegenerative disorder and the most common type of advanced dementia worldwide. Although it is lifestyle-dependent, it is mostly observed in individuals over the age of 65 and is characterized by amnesia in its advanced stages.</p><p>Alzheimer's disease has a multifactorial nature. The main pathological mechanisms of the disease are amyloid β plaque and neurofibrillary tangle formation and decreased cholinergic transmission. Loss of function is also intense in the brain regions where the pathological mechanisms leading to neurodegeneration occur intensely. Although mild cognitive impairments are observed in the initial stages of the disease, more severe symptoms are observed in advanced stages. AChE inhibitors improve memory disorders by increasing cholinergic transmission. Currently, there are 3 AChE enzyme inhibitors approved by the FDA for the treatment of the disease. With the elucidation of the role of BChE in the pathology of the disease, dual inhibitors targeting both AChE and BChE have started to be designed.</p><p>Myasthenia gravis is an autoimmune neuromuscular junction disease that leads to skeletal muscle weakness. The muscles most commonly affected by the disease in the body are the eye, face and swallowing muscles. Cholinesterase inhibition often provides symptomatic relief from muscle weakness and cholinesterase inhibitors are included in treatment.</p><p>Glaucoma describes visual disturbances due to damage to the optic nerve, which can lead to vision loss. Glaucoma is usually caused by a build-up of fluid in the front of the eye, which increases the pressure inside. Galantamine, a cholinesterase inhibitor, is known to relieve glaucoma symptoms by reducing intraocular pressure.</p><p>As a result of the literature review, it has been understood that dual inhibition of AChE and BChE enzymes in the central nervous system provides symptomatic improvement in Alzheimer's disease, and inhibition of these enzymes in the peripheral nervous system provides symptomatic improvement in myasthenia gravis and glaucoma. Within the scope of the thesis, the design, synthesis and bioactivity studies of a pyridinium derivative compound with the potential to inhibit AChE and BChE enzymes were carried out. According to the cholinesterase inhibitory activity results of the compound, it is highly active against both AChE and BChE enzymes and inhibits these enzymes at low µM concentrations. The data of the synthesized compound are reported for the first time in this study.</p>