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“Design, Synthesis and Biological Evaluation of Novel Coumarin Derivatives Targeting Acetylcholinesterase As Neuroprotective Against Alzheimer's Disease”

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“Design, Synthesis and Biological Evaluation of Novel Coumarin Derivatives Targeting Acetylcholinesterase As Neuroprotective Against Alzheimer's Disease” “Design, synthesis and biological evaluation of novel coumarin derivatives targeting acetylcholinesterase as neuroprotective against Alzheimer's disease” Thesis Presented by Haidy Hany Abdel Momen Abdel Hamid El-Zoheiry B.Sc., Faculty of Pharmacy, Cairo University (2013) Submitted in Partial Fulfillment of Master Degree In Pharmaceutical Sciences (Pharmaceutical Chemistry) Under the supervision of Prof. Dr. Kamilia Mahmoud Amin Professor of Pharmaceutical Chemistry Faculty of Pharmacy Cairo University Prof. Dr. Doaa Ezzat Abdel Rahman Professor of Pharmaceutical Chemistry Faculty of Pharmacy Cairo University Dr. Heba Abdel-Rasheed Allam Lecturer of Pharmaceutical Chemistry Faculty of Pharmacy Cairo University Cairo University (2019) 1 Abstarct Design, synthesis and biological evaluation of novel coumarin derivatives targeting acetylcholinesterase as neuroprotective against Alzheimer's disease Alzheimer’s disease (AD) is a neurodegenerative disease characterized by loss of memory and cognitive abilities. According to cholinergic hypothesis, reduced levels of acetylcholine (ACh) is contributed significantly to the cognitive symptoms associated with AD and advanced age. Accordingly, the mainstream direction for AD therapy is slowing the breakdown of ACh by the use of acetylcholinesterase inhibitors (AChEIs). Primarily, AChEIs have been considered only as a symptomatic therapy for AD, however recent studies have suggested that AChEIs can act as disease- modifying agents by inhibition of the amyloid cascade. Coumarin is an interesting bioactive scaffold eliciting a wide range of biological activities including anticancer, antibacterial, anti-inflammatory and anticoagulant. A structural survey of AChEIs revealed that a number of naturally occurring and synthetic coumarin analogues exhibited potent AChE inhibitory activity. Among these inhibitors AP2238 and ensaculin which have distinct scaffold with a coumarin moiety. Moreover, it has been demonstrated that AChEIs with coumarin moiety primarily interact with the peripheral anionic site (PAS) of AChE. These findings prompt medicinal chemists to design dual inhibitors of AChE by incorporating a catalytic site interacting moiety with coumarin through an appropriate linker. In this regard, we highlighted on the AChE inhibitory activity of the coumarin nucleus notably 7-benzyloxycoumarin derivatives. In this work, novel 7-benzyloxycoumarin based compounds were synthesized with a variety of bioactive chemical fragments which possess AChE 2 inhibitory activity. Moreover, in vitro acetylcholinesterase inhibition study was conducted according to modified Ellman’s method besides scopolamine induced dementia in vivo assay on the most active compounds. Furthermore, in silico studies were performed on the synthesized compounds which included molecular docking study at the active site of recombinant human acetylcholinesterase enzyme (rhAChE) as well as prediction of ADMET and pharmacokinetic parameters. The thesis includes the following sections: 1. Introduction This section presents a brief literature review about Alzheimer’s disease, its pathogenesis and treatment besides a review on acetylcholinesterase and its inhibitors. In addition, a survey on the different biological activities of coumarin compounds with special emphasis on their acetylcholinesterase inhibitory activity is included. 2. Aim of the work This section illustrates the scientific basis upon which the synthesized compounds were designed. 3. Theoretical discussion This section deals with the discussion of the experimental methods adopted for the synthesis of the designed compounds in addition to a summarized data for the characterization and verification of the new compounds structures using different spectroscopic methods. 4. Experimental part This section describes the practical procedures used for the synthesis of the published compounds, the new intermediates and the new final compounds. In 3 addition, physical, elemental analyses and spectral data (IR, 1H-NMR, 13C-NMR and mass spectroscopy) are cited. Published compounds: 7-Hydroxy-4-methyl-2H-chromen-2-one (I) 7-Benzyloxy-4-methyl-2H-chromen-2-one (II) 7-Benzyloxy-2-oxo-2H-chromene-4-carbaldehyde (III) 2-(7-Hydroxy-2-oxo-2H-chromen-4-yl)acetic acid (X) Methyl-2-(7-hydroxy-2-oxo-2H-chromen-4-yl)acetate (XI) 2-(7-Benzyloxy-2-oxo-2H-chromen-4-yl)acetohydrazide (XIII) New intermediate compounds: 1-[(7-Benzyloxy-2-oxo-2H-chromen-4-yl)methylene]thiosemicarbazide (IV) Methyl 2-(7-benzyloxy-2-oxo-2H-chromen-4-yl)acetate (XII) New final compounds: 7-Benzyloxy-4-{[(4-methylthiazol-2(3H)-ylidene)hydrazono]methyl}-2H- chromen-2-one (V) 7-Benzyloxy-4-{[(4-phenylthiazol-2(3H)-ylidene)hydrazono]methyl}-2H- chromen-2-one (VIa) 7-Benzyloxy-4-({[4-(4-bromophenyl)thiazol-2(3H)-ylidene]hydrazono} methyl)-2H-chromen-2-one (VIb) 7-Benzyloxy-4-({[4-(4-methoxyphenyl)thiazol-2(3H)-ylidene]hydrazono} methyl)-2H-chromen-2-one (VIc) Ethyl-2-{2-[(7-benzyloxy-2-oxo-2H-chromen-4-yl)methylene]hydrazono} -4-methyl-2,3-dihydrothiazole-5-carboxylate (VII) 2-{2-[(7-Benzyloxy-2-oxo-2H-chromen-4-yl)methylene]hydrazono} thiazolidin-4-one (VIII) 2-(2-{[(7-Benzyloxy-2-oxo-2H-chromen-4-yl)methylene]hydrazono}-4- oxothiazolidin-5-yl)acetic acid (IX) 4 2-(7-Benzyloxy-2-oxo-2H-chromen-4-yl)-N-(2,5-dioxopyrrolidin-1- yl)acetamide (XIVa) 2-(7-Benzyloxy-2-oxo-2H-chromen-4-yl)-N-(2,5-dioxo-2,5-dihydro-1H- pyrrol-1-yl)acetamide (XIVb) 2-(7-Benzyloxy-2-oxo-2H-chromen-4-yl)-N-(1,3-dioxoisoindolin-2- yl)acetamide (XIVc) 1-[2-(7-Benzyloxy-2-oxo-2H-chromen-4-yl)acetyl]-4-methyl thiosemicarbazide (XVa) 1-[2-(7-Benzyloxy-2-oxo-2H-chromen-4-yl)acetyl]-4-phenyl thiosemicarbazide (XVb) 2-(7-Benzyloxy-2-oxo-2H-chromen-4-yl)-N’-(3-methyl-4-oxothiazolidin-2- ylidene)acetohydrazide (XVI) 2-(7-Benzyloxy-2-oxo-2H-chromen-4-yl)-N-(2-methylimino-4- phenylthiazol-3(2H)-yl)acetamide (XVIIa) 2-(7-Benzyloxy-2-oxo-2H-chromen-4-yl)-N-[4-(4-methoxyphenyl)-2- methyliminothiazol-3(2H)-yl]acetamide (XVIIb) 4-[(4-Amino-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-7- benzyloxy-2H-chromen-2-one (XVIII) 1-[2-(7-Benzyloxy-2-oxo-2H-chromen-4-yl)acetyl]-3-methyl-1,2- dihydropyrazol-5-one (XIX) 7-Benzyloxy-4-[2-(3,5-dimethyl-1H-pyrazol-1-yl)-2-oxoethyl]-2H-chromen- 2-one (XX) 5-Amino-1-[2-(7-benzyloxy-2-oxo-2H-chromen-4-yl)acetyl]-1H-pyrazole-4- carbonitrile (XXI) 5. Biological evaluation This section includes the procedures and discussion of the results of the in vitro acetylcholinesterase inhibitory activity against donepezil as a reference drug 5 in addition to scopolamine induced dementia in vivo assay on the most active compounds VIa, XVIIa and XXI to investigate their behavior study. 6. Molecular modeling studies 6.1. Molecular docking study This section includes molecular docking of the synthesized compounds on the active site of acetylcholinesterase to explore their binding mode of interaction as well as their amino acids binding interactions. 6.2. Physicochemical, ADMET and pharmacokinetic properties prediction This section includes prediction of distribution and toxicity parameters of the synthesized compounds where most of the compounds explored good pharmacokinetic profile. 7. References This part includes 221 references covering the period of 1904 to 2019. 8. Arabic summary 6 Introduction 1.1. Alzheimer’s disease: Alzheimer’s disease (AD) was identified more than 100 years ago when Alois Alzheimer first published a case of "presenile dementia" in a female patient named Auguste Deter who died in a completely demented state. AD is a neurodegenerative brain disease which is the most common cause of dementia and is ultimately fatal.(1) Dementia is characterized by a decline in memory, language, problem solving and other cognitive skills that affects a person’s ability to perform everyday activities. This decline occurs because nerve cells in parts of the brain involved in cognitive function have been damaged. The damage of neurons eventually affects other parts of the brain including those that enable a person to carry out basic bodily functions such as walking and swallowing. Unfortunately, people in the final stages of this disease are bed-bound and require around-the- clock care.(2) It is well known that, the primary risk factors of AD are aging, family history and genetics. According to Alzheimer’s Association annual report in 2018, 10% of people older than 65 years old and 50% of people older than 85 years old are easily affected by AD. Apart from these statistics, people younger than 65 years old may be affected by Familial Alzheimer’s disease (FAD) in which gene mutations are the foremost cause.(3) 1.2. Pathology of Alzheimer’s disease: The two most common hypotheses used to describe the pathology of AD are known as "amyloid hypothesis" and "cholinergic hypothesis".(4) 1.2.1. Cholinergic hypothesis: The cholinergic hypothesis was formulated approximately 30 years ago. It stated that a serious loss of cholinergic function in the central nervous system 7 (CNS) contributed significantly to the cognitive symptoms associated with AD and advanced age. This loss in cholinergic function is due to deficiency in choline acetyltransferase enzyme (ChAT) which is responsible for the synthesis of acetylcholine (ACh) in addition to the reduction of choline uptake and ACh release. Thus, a sharp decrease in the neurotransmitter ACh in brain synapses specifically in amygdala and hippocampus was the most consistent neurochemical finding in diseased brains that lead to the cholinergic hypothesis.(11,12) It is well known
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