Design and synthesis of novel coumarin derivatives as potential acetylcholinesterase inhibitors for Alzheimer's disease. 2021

Kamilia M Amin, and Doaa E Abdel Rahman, and Heba Abdelrasheed Allam, and Haidy H El-Zoheiry
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo 11562, Egypt.

Twenty novel 7-benzyloxycoumarin based compounds were synthesized with a variety of bioactive chemical fragments. The synthesized compounds showed remarkable acetylcholinesterase (AChE) inhibitory activity. In vitro assay revealed that compounds 7-benzyloxy-4-{[(4-phenylthiazol-2(3H)-ylidene)hydrazono]methyl}-2H-chromen-2-one (5b, IC50= 0.451μM), 7-benzyloxy-4-({[4-(4-methoxyphenyl)thiazol-2(3H)-ylidene]hydrazono}methyl)-2H-chromen-2-one (5d, IC50= 0.625μM), 5-amino-1-[2-(7-benzyloxy-2-oxo-2H-chromen-4-yl)acetyl]-1H-pyrazole-4-carbonitrile (13c, IC50= 0.466μM), 2-(7-benzyloxy-2-oxo-2H-chromen-4-yl)-N-(2-methylimino-4-phenylthiazol-3(2H)-yl)acetamide (16a, IC50= 0.500μM) and 2-(7-benzyloxy-2-oxo-2H-chromen-4-yl)-N-[4-(4-methoxyphenyl)-2-methyliminothiazol-3(2H)-yl]acetamide (16b, IC50= 0.590μM) exhibited promising AChE inhibitory activity even better than donepezil (IC50= 0.711μM). Kinetic study for compound 5b implied mixed type inhibitor which could bind peripheral anionic site (PAS) and catalytic active site (CAS) of AChE enzyme. In addition, in vivo evaluation of compounds 5b, 13c and 16a confirmed significant memory improvement in scopolamine-induced impairment model in tested mice. 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 other physicochemical parameters. A correlation between the docking results and IC50 of tested compounds was routinely observed and shared similar binding pattern to the co-crystallized ligand donepezil.

UI MeSH Term Description Entries
D008297 Male Males
D008807 Mice, Inbred BALB C An inbred strain of mouse that is widely used in IMMUNOLOGY studies and cancer research. BALB C Mice, Inbred,BALB C Mouse, Inbred,Inbred BALB C Mice,Inbred BALB C Mouse,Mice, BALB C,Mouse, BALB C,Mouse, Inbred BALB C,BALB C Mice,BALB C Mouse
D002800 Cholinesterase Inhibitors Drugs that inhibit cholinesterases. The neurotransmitter ACETYLCHOLINE is rapidly hydrolyzed, and thereby inactivated, by cholinesterases. When cholinesterases are inhibited, the action of endogenously released acetylcholine at cholinergic synapses is potentiated. Cholinesterase inhibitors are widely used clinically for their potentiation of cholinergic inputs to the gastrointestinal tract and urinary bladder, the eye, and skeletal muscles; they are also used for their effects on the heart and the central nervous system. Acetylcholinesterase Inhibitor,Acetylcholinesterase Inhibitors,Anti-Cholinesterase,Anticholinesterase,Anticholinesterase Agent,Anticholinesterase Agents,Anticholinesterase Drug,Cholinesterase Inhibitor,Anti-Cholinesterases,Anticholinesterase Drugs,Anticholinesterases,Cholinesterase Inhibitors, Irreversible,Cholinesterase Inhibitors, Reversible,Agent, Anticholinesterase,Agents, Anticholinesterase,Anti Cholinesterase,Anti Cholinesterases,Drug, Anticholinesterase,Drugs, Anticholinesterase,Inhibitor, Acetylcholinesterase,Inhibitor, Cholinesterase,Inhibitors, Acetylcholinesterase,Inhibitors, Cholinesterase,Inhibitors, Irreversible Cholinesterase,Inhibitors, Reversible Cholinesterase,Irreversible Cholinesterase Inhibitors,Reversible Cholinesterase Inhibitors
D003374 Coumarins Synthetic or naturally occurring substances related to coumarin, the delta-lactone of coumarinic acid. 1,2-Benzopyrone Derivatives,1,2-Benzopyrones,Coumarin Derivative,Coumarine,1,2-Benzo-Pyrones,Benzopyran-2-ones,Coumarin Derivatives,Coumarines,1,2 Benzo Pyrones,1,2 Benzopyrone Derivatives,1,2 Benzopyrones,Benzopyran 2 ones,Derivative, Coumarin,Derivatives, 1,2-Benzopyrone,Derivatives, Coumarin
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000110 Acetylcholinesterase An enzyme that catalyzes the hydrolysis of ACETYLCHOLINE to CHOLINE and acetate. In the CNS, this enzyme plays a role in the function of peripheral neuromuscular junctions. EC 3.1.1.7. Acetylcholine Hydrolase,Acetylthiocholinesterase,Hydrolase, Acetylcholine
D000544 Alzheimer Disease A degenerative disease of the BRAIN characterized by the insidious onset of DEMENTIA. Impairment of MEMORY, judgment, attention span, and problem solving skills are followed by severe APRAXIAS and a global loss of cognitive abilities. The condition primarily occurs after age 60, and is marked pathologically by severe cortical atrophy and the triad of SENILE PLAQUES; NEUROFIBRILLARY TANGLES; and NEUROPIL THREADS. (From Adams et al., Principles of Neurology, 6th ed, pp1049-57) Acute Confusional Senile Dementia,Alzheimer's Diseases,Dementia, Alzheimer Type,Dementia, Senile,Presenile Alzheimer Dementia,Senile Dementia, Alzheimer Type,Alzheimer Dementia,Alzheimer Disease, Early Onset,Alzheimer Disease, Late Onset,Alzheimer Sclerosis,Alzheimer Syndrome,Alzheimer Type Senile Dementia,Alzheimer's Disease,Alzheimer's Disease, Focal Onset,Alzheimer-Type Dementia (ATD),Dementia, Presenile,Dementia, Primary Senile Degenerative,Early Onset Alzheimer Disease,Familial Alzheimer Disease (FAD),Focal Onset Alzheimer's Disease,Late Onset Alzheimer Disease,Primary Senile Degenerative Dementia,Senile Dementia, Acute Confusional,Alzheimer Dementias,Alzheimer Disease, Familial (FAD),Alzheimer Diseases,Alzheimer Type Dementia,Alzheimer Type Dementia (ATD),Alzheimers Diseases,Dementia, Alzheimer,Dementia, Alzheimer-Type (ATD),Familial Alzheimer Diseases (FAD),Presenile Dementia,Sclerosis, Alzheimer,Senile Dementia
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001522 Behavior, Animal The observable response an animal makes to any situation. Autotomy Animal,Animal Behavior,Animal Behaviors

Related Publications

Kamilia M Amin, and Doaa E Abdel Rahman, and Heba Abdelrasheed Allam, and Haidy H El-Zoheiry
May 2013, Bioorganic & medicinal chemistry letters,
Kamilia M Amin, and Doaa E Abdel Rahman, and Heba Abdelrasheed Allam, and Haidy H El-Zoheiry
December 2017, Journal of enzyme inhibition and medicinal chemistry,
Kamilia M Amin, and Doaa E Abdel Rahman, and Heba Abdelrasheed Allam, and Haidy H El-Zoheiry
June 2017, Journal of biomolecular structure & dynamics,
Kamilia M Amin, and Doaa E Abdel Rahman, and Heba Abdelrasheed Allam, and Haidy H El-Zoheiry
January 2017, Anti-cancer agents in medicinal chemistry,
Kamilia M Amin, and Doaa E Abdel Rahman, and Heba Abdelrasheed Allam, and Haidy H El-Zoheiry
March 2020, Bioorganic chemistry,
Kamilia M Amin, and Doaa E Abdel Rahman, and Heba Abdelrasheed Allam, and Haidy H El-Zoheiry
October 2016, Bioorganic & medicinal chemistry,
Kamilia M Amin, and Doaa E Abdel Rahman, and Heba Abdelrasheed Allam, and Haidy H El-Zoheiry
February 2024, Bioorganic chemistry,
Kamilia M Amin, and Doaa E Abdel Rahman, and Heba Abdelrasheed Allam, and Haidy H El-Zoheiry
February 2014, Bioorganic & medicinal chemistry,
Kamilia M Amin, and Doaa E Abdel Rahman, and Heba Abdelrasheed Allam, and Haidy H El-Zoheiry
November 2013, Archiv der Pharmazie,
Kamilia M Amin, and Doaa E Abdel Rahman, and Heba Abdelrasheed Allam, and Haidy H El-Zoheiry
May 2016, Bioorganic & medicinal chemistry letters,
Copied contents to your clipboard!