Yeni β–amiloid agregasyon inhibitörü bileşikler üzerinde sentez ve biyoaktivite çalışmaları
Yükleniyor...
Tarih
2018
Yazarlar
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Ege Üniversitesi, Sağlık Bilimleri Enstitüsü
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Alzheimer's Disease (AD) is characterized by impaired memory, cognition and behavior. AH is a progressive and irreversible neurodegenerative disease and is the most common form of dementia. Dementia is one of the most common diseases in the elderly. AH is the fifth leading cause of death in the United States for aged 65 and older elderly population. In the pathology of AD; extracellular plaques composed of beta amyloid (Aβ) peptide, intracellular neurofibrillary tangles (NFY) consisting of abnormal phosphorylated tau protein, gliosis-inflammation as well as neuronal, synaptic and cholinergic loss play a role. According to the hypothesis, called "Amyloid Cascade Hypothesis", the main pathological event that initiates the disease is the accumulation of Aβ-peptide. Currently, acetylcholinesterase (AChE) inhibitors (donepezil, rivastigmine and galantamine) and N-methyl-D-aspartate (NMDA) receptor antagonists (memantine) are used in the treatment of AH. Until now, no drug or application has succeeded in completely treating AH. Therapeutic strategies targeted against Aβ accumulation corresponding to the present symptomatic treatments are therefore carefully investigated. Among the most effective treatment strategies against this pathology is the inhibition of Aβ peptide. Rifampicin, congo red (CR), chrysamine-G (CG) and curcumin compounds which are reported to decrease A-neurotoxicity, are small molecule inhibitors used in the treatment of AH. Based on the structural properties of these compounds, synthesis of 28 compounds in two series, imine and azo series, was carried out in the thesis study. For the synthesis of imine series compounds; [1,1′-biphenyl]-4,4′-diyldimethanol was reacted with pyridinium chlorochromate (PCC) at room temperature to give 4,4′-biphenyldialdeyhde intermediate. The imine derivatives were synthesized as a result of the condensation reaction of the intermediate with the appropriate amines. Azo series compounds were obtained in a single step in which the redox reaction of the 4,4′-dinitrobiphenyl compound with the appropriate amines in the presence of the base was carried out. The structures of the synthesized compounds were elucidated by spectroscopic methods (IR, 1H-NMR, LC/MS) and elemental analysis. The cholinesterase (ChE) inhibition of these compounds (Ellman's test) and the inhibition of Aβ42 aggregation (thioflavine T fluorescence assay) were evaluated together. The partition coefficient (Log P) and acid dissociation constant (pKa) of the compounds were calculated by potentiometric titration method. As a result of the ChE inhibition studies on the obtained compounds, it was found that the compounds are selective for AChE enzyme. The highest activity against AChE in the synthesized compounds is the azo-14 coded compound (IC50= 5.77 ± 0.20 μМ) when compared to the tacrine and galantamine used as reference compounds; the highest activity against butyrylcholinesterase (BuChE) was the azo-11 coded compound (IC50= 2.72 ± 0.15 μМ). In the studies of inhibition of Aβ42 aggregation, the % inhibition results of the compounds at 100 μM were observed in the range of 6.55-78.39 %. The azo-9 coded compound was found to be the most effective compound on inhibition of Aβ aggregation (78.39 % at 100 μM) by exhibiting activity close to the reference compound curcumin. The azo series compounds exhibit a more effective Aβ aggregation inhibition profile than the imine series compounds. In recent years, studies on anti-Alzheimer's have merged into the view that direction to multi-targeted treatment strategies may lead to positive outcomes in the prevention and treatment of disease progression. When the ChE and Aβ aggregation inhibition activities on the compounds in the thesis are evaluated together, it has been concluded that the azo series compounds can act as multi-targeted agents.
Açıklama
Anahtar Kelimeler
Alzheimer Hastalığı, β-Amiloid, Sentez, Kolinesteraz İnhibisyonu, Aβ Agregasyon İnhibisyonu, Alzheimer's Disease, β-Amyloid, Synthesis, Cholinesterase Inhibition, Aβ Aggregation Inhibition
