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Acetylcholine (ACh) neurotransmitter of the cholinergic system in the brain is involved in learning, memory, stress responses, and cognitive functioning. It is hydrolyzed into choline and acetic acid by two key cholinesterase enzymes, viz., acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). A loss or degeneration of cholinergic neurons that leads to a reduction in ACh levels is considered a significant contributing factor in the development of neurodegenerative diseases (NDs) such as Alzheimer's disease (AD). Numerous studies have shown that cholinesterase inhibitors can raise the level of ACh and, therefore, enhance people's quality of life, and, at the very least, it can temporarily lessen the symptoms of NDs. 1,2,3-triazole, a five-membered heterocyclic ring, is a privileged moiety, that is, a central scaffold, and is capable of interacting with a variety of receptors and enzymes to exhibit a broad range of important biological activities. Recently, it has been clubbed with other pharmacophoric fragments/molecules in hope of obtaining potent and selective AChE and/or BuChE inhibitors. The present updated review succinctly summarizes the different synthetic strategies used to synthesize the 1,2,3-triazole moiety. It also highlights the anticholinesterase potential of various 1,2,3-triazole di/trihybrids reported in the past seven years (2015–2022), including a rationale for hybridization and with an emphasis on their structural features for the development and optimization of cholinesterase inhibitors to treat NDs. [ABSTRACT FROM AUTHOR]

[Display omitted] Alzheimer's disease (AD) is one of the most common and prevalent forms of neurodegenerative diseases. Coumarin is a versatile scaffold that exhibits a wide range of biological properties including cholinesterase inhibitory activity and therefore is an important heterocyclic moiety to develop anti-AD drugs. This study aimed to design and synthesize coumarin linked 1,3,4-oxadiazole hybrid derivatives as multi-target directed ligands (MTDLs) and to investigate their in vitro anticholinesterase, antioxidant and anti-inflammatory activities. Two series (4a-n and 7a-m) of low molecular weight ligands (27 compounds) containing coumarin linked 1,3,4-oxadiazole hybrids were synthesized and their chemical structures were characterized using analytical data. In vitro acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) inhibitory activity, antioxidant activity and cyclooxygenase (COX) inhibitory activity were investigated following standard spectrophotometric methods. Molecular docking studies to predict the binding mode with AChE and BuChE in addition to the pharmacokinetic profile of the synthesized compounds were studied with the help of online cheminformatics software. Amongst the tested compounds for anticholinesterase activity, 4e and 4g hybrid derivatives were found to be the most potent AChE inhibitors (IC 50 values = 29.56 and 28.68 μM), respectively. Compound 4m exhibited the maximum inhibitory activity against BuChE (IC 50 value = 23.97 μM). Compounds 4g and 4e also showed higher selectivity index (SI) of 1.652 and 1.552 as compared to standard galantamine (SI = 1.132). Molecular docking studies revealed that 4g and 4e, two most potent AChE inhibitors identified through in vitro assay, binds well to AChE (binding energy scores of −9.7 and −10.1 Kcal/Mol). Synthesized hybrid molecules also exhibited good to excellent in vitro antioxidant and anti-inflammatory activities. Based on the results of in vitro and in-silico studies, it could be concluded that coumarin-oxadiazole hybrids acts as MTDLs and are promising source of anti-AD drugs. Further detailed investigations and modification of these compounds can lead to the development of highly potent therapeutics for the treatment of AD. [ABSTRACT FROM AUTHOR]

• Hybridization drug design strategies with rationale to obtain multi target directed ligands (MTDLs) as anti-Alzheimer drugs. • The review covers SAR studies for further development of coumarin-hybrids as therapeutic agents for the Alzheimer's disease (AD). • It provides an overview of research work carried out on di and tri-hybridized coumarin conjugates during 2010–2020. • Chemical structure and biochemical targets of naturally occurring coumarin derivatives with anti-AD properties. • Patents granted to coumarin derivatives for AD treatment. Alzheimer's disease (AD) is a major progressive and perplexing cortical degenerative disease of the brain in the elderly. It contributes to a significant socioeconomic burden on patients, families, and care providers in comparison to cancer, cardiovascular diseases, and stroke in general. Recently, a hybridized approach based on multi-target directed ligands (MTDLs) has received considerable attention to develop therapeutic agents for AD which act at multiple targets. Approximately 20% of the drugs approved in the past couple of years were developed using the same strategy and thus it seems to be the right approach to develop AD therapy. The comprehensive and updated review on coumarin hybrids as MTDLs in AD therapy is compiled using several electronic databases such as Scopus, Google Scholar, SciFinder, Mendeley, and PubMed. The research studies published on coumarin hybrids in the last decade (2010- 2020) have been covered in this review article. This updated review highlights the importance of coupling (hybridization) coumarin scaffold with other bioactive pharmacophores to develop MTDLs for AD therapy. It also covers the patents granted to coumarin derivatives for AD treatment, natural products containing coumarin scaffold with anti-Alzheimer spectrum, the rationale for coupling pharmacophore fragments, detailed structure activity relationship (SAR), and molecular docking studies. The most potent and promising hybrid compounds have also been identified for further development of AD drugs. Authors are of the opinion that hybridization strategy would soon yield drug candidates for the treatment of AD. [ABSTRACT FROM AUTHOR]