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Alzheimer's disease (AD) is a progressive neurodegenerative disease that still has no permanent cure. The drugs prescribed in the present days are only for symptomatic relief for the patients. Many studies correlating the reduction in the incidence of AD with the diet consumed have been published. These studies showed that a diet rich in polyphenols is associated with a decrease in the incidence of AD. The present review is focused on the ability of pomegranate and its bioactive components to ameliorate the progression of AD and their ability to exert a neuroprotective effect. Various studies showing the ability of pomegranate in inhibiting enzymes, reducing reactive oxygen species, inhibition of microglial activation, inhibition of tau protein hyperphosphorylation, maintenance of synaptic plasticity, anti-inflammatory activity and its ability to inhibit Beta secretase-1 (BACE-1) has been reviewed in this article. In spite of the lack of studies on humans, there are compelling evidence indicating that pomegranate can reduce various risk factors involved in the causation of AD and thus can be used as a persistent nutraceutical to slow ageing and for providing neuroprotection for the treatment of AD. Highlights An overview of traditional and pharmacological uses of pomegranate (POM). Potential of POM in the treatment of neurodegenerative diseases especially in AD. Insight into the molecular mechanisms of neuroprotective effects of POM in AD. Clinical evaluation studies involving POM and its bioactive components. [ABSTRACT FROM AUTHOR]

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]

Alzheimer's disease (AD) is an irreversible progressive neurodegenerative disease. Punica granatum L., (P. granatum) is one of the most important commercial crops of Oman with traditional medicinal claims. The study aimed to quantify the phenolic content of the Omani pomegranate peel extracts and to investigate their antioxidant, anti-cholinesterase activities along with computational studies for the development of AD therapy. The dried peels of P. granatum fruits were exhaustively extracted with chloroform, ethyl acetate and butanol. Peel extracts were subjected to the preliminary phytochemical screening. Colorimetric methods were used to quantify total phenolic and flavonoids contents. The neuroprotective potential of the peel extracts was evaluated by assessing the in-vitro antioxidant activity and their ability to inhibit acetylcholinesterase (AChE) enzyme activity. In-silico analysis and molecular docking of the most promising phenolic metabolite present in pomegranate peel was also carried out. The phytochemical screening showed the presence of flavonoids, tannins, alkaloids, carbohydrates and terpenoids. The total phenolic, flavonoids content & antioxidant activity was found to be higher in the butanol extract. Surprisingly, butanol extract showed slightly lower AChE inhibitory activity than chloroform extract. Catechin, a polyphenolic compound present in the peel showed lower binding energy for AChE in comparison to Beta-secretase-1 (BACE-1). It formed three and two hydrogen bonds with AChE and BACE-1, respectively. The results of the current study provided evidence that butanol extract is rich in phenolics and possesses excellent antioxidant activity. Furthermore, in silico and in-vitro studies conducted on P. granatum revealed promising anti-AD activity. Further investigations must be carried out to isolate and develop the chemical constituents of pomegranate peel as neuroprotective agent(s). [Display omitted] • Phytochemical screening and quantification of phenolic compounds in an agro-waste. • Evaluation of antioxidant and anticholinesterase activity of pomegranate peel extracts. • In silico studies and molecular docking studies on the polyphenolic compounds found in pomegranate peel. • Butanol solvent was found to be optimum for the isolation of polyphenolic compounds. • Pomegranate peel could be used as an alternative source of natural antioxidants. [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]