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Abstract: Pyrimidine is an aromatic and heterocyclic organic compound containing a 6-membered ring consisting of four carbon and two nitrogen atoms on alternative positions. Pyrimidine scaffolds described theirexistence inthe medicinal chemist’s cause for their synthesizing practicability and nonpoisonous nature. However, the reason behind neurological disorders is still an open challenge for scientific research and development organizations. Efficacy voids are widespread before researchers, despite high throughput research in the field of anti-Alzheimer's drugs.Researchers have constantly investigated all the probabilities for restraining the unwanted adverse effects of the anti-Alzheimer’s agents and are focusing more extensively to rehabilitate neurological disorders. The scientific literature on drug development has been an aspiration to medicinal chemists and other researchers to facilitate further research. Therefore, this review emphasizes the structure-activity relationship (SAR) based approach and the pharmacological advancements of pyrimidine moiety in the new era of therapeutics as anti-Alzheimer’s agents.

Abstract: Dementia is a chronic neurodegenerative disease, and a maximum number of the cases are directly related to Alzheimer’s disease. More than 4 million people are living with Alzheimer’s disease-related dementia in India, making it a national crisis. Alzheimer’s disease deteriorates cognitive functions with the passage of time and consists of multi-faceted factors, such as the decline of acetylcholine level, amyloid β-aggregation, tau hyperphosphorylation, oxidative stress, etc. The classical drugs used to date, are focused on only one target and are not serving the cause properly. Hence, the community of scientists is rigorously working on multi-target-directed agents that incorporate two or more active scaffolds in one compound or hybrid of active moieties. This article aims to evaluate novel potential compounds and moieties, such as quinolines, chalcones, coumarins, chromenes, piperazine, carbazoles, cinnamic acids, tacrine hybrids, donepezil hybrids, etc., that have been introduced as multi-target-directed agents in the recent five years.

Quinoline and its derivatives comprise an important group of heterocyclic compounds that exhibits a wide range of pharmacological properties such as antibacterial, antiviral, anticancer, antiparasitic, anti-Alzheimer and anticholesterol. The quinoline nucleus is found in the structure of many drugs and rational design in medicinal chemistry for the discovery of novel bioactive molecules. Persistent efforts have been made over the years to develop novel congeners with superior biological activities and minimal potential for undesirable side effects. This review highlights some discoveries on the development of quinoline-based compounds in recent years (2013-2019), focusing on their biological activities, including anticancer, antitubercular, antimalarial, anti-ZIKV, anti-DENV, anti- Leishmania and anti-Alzheimer’s disease.

Background Uncaria tomentosa, which has similar chemical constituents with Uncaria rhynchophylla, has been reported to alleviate cognitive impairments in Alzheimer’s disease (AD) animal models. This study aimed to compare the chemical constituents and anti-AD effect of the ethanol extracts of U. tomentosa (UTE) and U. rhynchophylla (URE). Methods The high-performance liquid chromatography (HPLC) was used to compare the chemical constituents of UTE and URE. Streptozotocin (STZ) was intracerebroventricularly (ICV) injected into adult male Sprague–Dawley (SD) rats to establish AD model. UTE (400 mg/kg) or URE (400 mg/kg) was administrated intragastrically once daily to the rats for 6 consecutive weeks. Morris water maze (MWM) test was conducted to assess the neurological functions in the STZ-induced AD rats. The brain tissues of the rats were harvested for further biochemical assay. Results The MWM test results showed both UTE and URE could significantly improve the learning and memory impairments induced by STZ in rats. Both UTE and URE could significantly inhibit the hyperphosphorylation of tau protein, reduce the elevated levels of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α), enhance activities of antioxidant enzymes (SOD, CAT and GPx) and increase the protein expression of HO-1. In addition, UTE could decrease the malondialdehyde (MDA) level. Furthermore, both UTE and URE significantly enhanced Akt activation, down regulated the activation of glycogen synthase kinase 3β (GSK-3β), and induced the nuclear translocation of Nrf2 in the STZ-induced AD rats. Conclusions UTE and URE contained similar chemical constituents. We found for the first time that both of them could ameliorate cognitive deficits in the STZ-induced AD rats. The underlying molecular mechanism involve suppression of tau hyperphosphorylation, anti-oxidant and anti-neuroinflammation via modulating Akt (Ser473)/GSK3β (Ser9)-mediated Nrf2 activation. These findings amply implicate that both of UTE and URE are worthy of being developed clinically into pharmaceutical treatment for AD.

Background: One of the best methods to treat Alzheimer disease (AD) is through the effective use of cholinesterase inhibitors as vital drugs due to the identification of acetylcholine deficit in the AD patients. Objective: The present study aims the investigation of spiro heterocyclic compounds as potential AD agents supported by their metal chelation capacity, POM analyses and DFT studies, respectively. Methods: The cholinesterase inhibition and metal chelation ability were performed on ELISA microtiter assay. Whereas, the B3LYP method with 6-31+G(d,p) basis set was implemented to study HOMOLUMO energy calculations. The pharmacokinetic properties of the synthesized molecules were studied through Petra, Osiris and Molinspiration (POM). Results: The six spiro (1-6) skeletons were tested for their inhibitory potential and metal-chelation capacity. Our findings revealed that the tested spiro skeletons exerted none or lower than 50% inhibition against both cholinesterases, while compound 4 proved to be the most active molecule with 57.21±0.89% of inhibition toward BChE. The spiro molecule 3 exhibited the highest metal-chelation capacity (9.12±5.26%). Molecular docking model for the most active molecule exhibited promising bindings with AChE and BChE’s active site pertained to hydrophobic hydrogen bonds and positive ionizable interactions. The POM analyses gave the information about the flexibility at the site of coordination of spiro compounds (1-6). Conclusion: The screening of spirocompounds (1-6) against cholinesterases revealed that some of them show considerable potential to inhibit AChE and BChE. Herein, we propose that the spiro molecules after further derivatization could serve interesting AD inhibitor drugs.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with concealed onset, which is characterized by the damage of the cholinergic system, deposition, and accumulation of β- amyloid protein (Aβ) and neurofibrillary tangles. Because the cholinergic system plays a key role in the process of brain memory, it has become one of the important targets in anti-AD research. In view of the complicated pathological characteristics of AD, the multi-target directed ligands (MTDLs) that can act on multiple targets are considered to be an effective treatment strategy at present. Tacrine, as the first acetylcholinesterase (AChE) inhibitor, has been discontinued because of its hepatotoxicity, but its core structure is simple and easy to modify. By using tacrine to target the active catalytic site (CAS), the tacrine-based MTDLs can act on both CAS and peripheral anion site (PAS) of AChE to serve as a dual-site AChE inhibitor. Additionally, the tacrine-based MTDLs can also be designed on the basis of other theories of AD, for example, introducing functional moieties to modulate the formation of β-amyloid (Aβ), oxidation resistance, or metal chelation. In this paper, the research progress of tacrine-based MTDLs is summarized.

Background: Alzheimer’s disease (AD) increases societal costs and decreases the activities of daily living (ADL) and quality of life (QoL) of the affected individuals. Objective: We assess the impact of AD severity on ADL, QoL, and caregiving costs in Japanese facilities for the elderly. Methods: Patients with AD in facilities for the elderly were included (47 facilities, N = 3,461). The QoL, ADL, and disease severity of patients were assessed using Barthel Index (BI), EuroQoL-5D-5L (EQ-5D-5L), and Mini-Mental State Examination (MMSE), respectively. Annual caregiving costs were estimated using patients’ claims data. The patients were subcategorized into the following three groups according to the MMSE score: mild (21≤MMSE≤30), moderate (11≤MMSE≤20), and severe (0≤MMSE≤10). Changes among the three groups were evaluated using the Jonckheere-Terpstra test. Results: Four hundred and one participants were on anti-AD medicines, of whom 287 (age: 86.1±6.4 years, 76.7% women) in the mild (n = 53, 84.0±6.9 years, 71.7%), moderate (n = 118, 86.6±5.9 years, 76.3%), and severe (n = 116, 86.6±6.5 years, 79.3%) groups completed the study questionnaires. The mean BI and EQ-5D-5L scores for each group were 83.6, 65.1, and 32.8 and 0.801, 0.662, and 0.436, respectively. The mean annual caregiving costs were 2.111, 2.470, and 2.809 million JPY, respectively. As AD worsened, the BI and EQ-5D-5L scores decreased and annual caregiving costs increased significantly. Conclusion: AD severity has an impact on QoL, ADL, and caregiving costs.

A series of 2-(3-hydroxybenzyl)benzo[d]isothiazol-3(2H)-one Mannich base derivatives were designed as potential multifunctional agents against Alzheimer’s disease. The twelve derivatives were synthesized and evaluated with various biological activities. In vitro, biological assays showed that most of the target compounds are selective AChE inhibitors and good antioxidants. Among them, compounds 6d and 13d are representative agents exhibiting significant selective AChE inhibition (IC50 = 1.09 µM and 2.01 µM, respectively), potent antioxidant activity, moderate inhibition of self-induced Aβ1–42 aggregation, selective metal-chelating activity with Fe2+ and Cu2+, excellent neuroprotective effect on H2O2-induced PC12 cell injury and good BBB permeability. Moreover, the step-down passive avoidance test demonstrated that 6d and 13d can improve the scopolamine-induced cognitive deficit in mice. The above results suggested that compounds 6d and 13d can be envisioned as multifunctional lead compounds for further development of drugs against AD.

In this study, a rapid and highly efficient method was developed for the separation of eight isoquinoline alkaloids using supercritical fluid chromatography. The separation conditions were carefully optimized including stationary phases, additives, backpressure, and temperature. Compared to high-performance liquid chromatography, the use of supercritical fluid chromatography could provide a 13 times faster separation. Subsequently, the method was validated and applied for the determination of eight alkaloids from different parts of Mahonia bealei (Fort.) Carr. (stem, root, leaf, and seed). The results indicated a good repeatability with relative standard deviations for overall precisions lower than 3.2%. The limit of detection was between 0.4 and 2.3 μg/mL while limit of quantitation ranged from 1.5 to 7.5 μg/mL. Recovery ranged from 95.7 to 102.5% indicating a validity of recovery. The content of total eight alkaloids was the highest in stem (66.0 μg/g) and root (65.1 μg/g) compared to leaf or seed. Moreover, anti-acetylcholinesterase activity for those extracts was evaluated by Ellman's colorimetric assay. As a result, the acetylcholinesterase inhibitory activity of the extracted samples was in the following decreasing order: stem > root > leaf or seed. In conclusion, the results indicated that supercritical fluid chromatography could be a useful tool for quality control of Mahonia bealei (Fort.) Carr. containing alkaloids as active compounds.

Background:: he incidence of dementia is increasing as the aging population of the world is increasing. Alzheimer’s disease (AD) is a neurodegenerative disorder of the central nervous system. There are presently 7.3 million patients of AD and the number may rise to 34 million at this pace in the coming thirty years. In the disease, the level of Acetylcholine is reduced and as a result, causes the loss of cholinergic neurons in the brain. The disease is less common in Asian countries as compared to the western nations of the world. This work aimed to establish the role of the common medicinal and food plants against Alzheimer's. Methods:: The enzyme acetylcholinesterase (AChE) is the enzyme responsible for hydrolysis and reduction of Acetylcholine. The anti-acetylcholinesterase activity of different extracts of three local plants used as spices in the daily food, Curcuma longa, Cinnnamomum tamala, and Zingiber officinale, was determined using the Microplate Assay method. Results:: The phytochemical study of the selected plants revealed the presence of alkaloids, terpenes, flavones, saponins, and tannins in these plants. The chloroform extract of all the three plants presented promising AChE inhibiting activity having IC50 >200μg/ml. A probable reason will be the alkaloids and terpenes present in the chloroform extract. Conclusion:: The chloroform extract of all three plants presented promising AChE inhibiting activity and can become a reasonable therapy for the cure/prevention of Alzheimer's disease. The frequent use of these spices may be a possible reason for the fever incidence of Alzheimer's in Asian countries. Further in vivo studies are required to find its action and studies to find the exact compound responsible for the action.

The last decide has witnessed a growing research interest in the role of dietary phytochemicals in influencing the gut microbiota. On the other hand, recent evidence reveals that dietary phytochemicals exhibit properties of preventing and tackling symptoms of Alzheimer's disease, which is a neurodegenerative disease that has also been linked with the status of the gut microbiota over the last decade. Till now, little serious discussions, however, have been made to link recent understanding of Alzheimer's disease, dietary phytochemicals and the gut microbiota together and to review the roles played by phytochemicals in gut dysbiosis induced pathologies of Alzheimer's disease. Deciphering these connections can provide insights into the development and future use of dietary phytochemicals as anti-Alzheimer drug candidates. This review aims at presenting latest evidence in the modulating role of phytochemicals in the gut microbiota and its relevance to Alzheimer's disease and summarizing the mechanisms behind the modulative activities. Limitations of current research in this field and potential directions will also be discussed for future research on dietary phytochemicals as anti-Alzheimer agents.

Objective: The current study aimed at the investigation of the effectiveness of ethanolic and methanolic extract of Polygonum glabrum in aluminum chloride-induced Alzheimer’s disease in experimental rats. Methods: The behavioral parameters evaluated by following methods such as Morris water maze test, radial arm maze test, and active avoidance test. Biochemical parameters were also estimated such as acetylcholine and acetylcholine esterase. Results: Polygonum glabrum extract was instituted to be neuroprotective against AlCl3-induced toxicity. Enhanced learning and memory were allied to the ingestion of extract in rats. Al overload, acetylcholinesterase enzyme hyperactivity is responsible for Alzheimer’s disease which is neutralized or reduced with treatment of extract, which might be due to the synergistic action of its active constituents. Ethanolic extract was shown slightly higher efficacy as compared to methanolic extract. Conclusion: Based on these current findings, it is suggested that lowering Aβ is an unproven strategy, and it may be time to refocus on other targets for the treatment of this disease, including pathological forms of tau.

Background: Curcumin, a providential spice, has its role in protecting the brain from neurodegeneration. Despite its ubiquitous role, it is not exploited alone due to its hampered bioavailability. By restraining the intestinal and liver enzymatic metabolism, one can boost the bioavailability of curcumin and promotes reabsorption of the curcumin. Diclofenac inhibits uridine 5'-diphosphoglucuronosyltransferase enzymes specifically responsible for the metabolism and elimination of curcumin. Lactobacillus rhamnosus is able to synthesize and release the β -d-glucuronidase enzyme, which reverts curcumin into the active form. Objective: In this research, we aim to combine curcumin with Lactobacillus rhamnosus and diclofenac as an adjuvant with curcumin to potentiate anti-Alzheimer effect in mice impaired with memory by scopolamine. Methods: To induce amnesia, scopolamine was used in mice model (1mg/kg, daily for 10 days i.p.). After execution of behavioural tests (Morris Water Maze test), brain and liver were isolated for further neurochemical and histopathology examination. Results: Our finding showed a marked rise in the level of antioxidant enzymes in curcumin with L. rhamnosus and diclofenac compared to curcumin alone. Additionally, the behavioural study revealed that cognition in mice with curcumin adjuvant with L. rhamnosus and diclofenac showed a marked improvement. The histology study proves that curcumin alone possesses less and a non-significant neuroprotective effect as compared to curcumin with L. rhamnosus and diclofenac. Conclusion: This entire outcome ratifies that curcumin with L. rhamnosus and diclofenac has higher activity as compared to curcumin alone, which reversed the cognition in the Alzheimer disease model.

Hyperforones A-J (1-10), ten degraded and reconstructed polycyclic polyprenylated acylphloroglucinols (PPAPs) with six different types of unusual architectures, were isolated from Hypericum perforatum (St. John's wort). Compound 1 is characterized by an unprecedented 1,5-epoxyfuro[3',4':1,5]cyclopenta[1,2-c]oxecine ring system; compounds 2 and 3 represent the first PPAPs with a contracted B-ring leading to the unique 5/5 core skeletons; compound 4, a proposed biosynthetic precursor of 2, is defined by an oxonane-2,7-dione architecture; compound 5 features an unusual spiro[furo[3',4':1,5]cyclopenta[1,2-b]oxepine-3,2'-oxetane] ring system; compounds 6-8 possess a rare macrocyclic lactone ring in addition to the newly formed C-ring; and compounds 9 and 10 contain a newly formed six-membered C-ring, which constructed the unexpected 6/6 scaffold with the B-ring. Hypothetic biosynthetic pathways to generate these scaffolds starting from the classic [3.3.1]-type PPAPs helped to elucidate their origins and validate their structural assignments. Compounds 4 and 6 simultaneously displayed notable activation of PP2A (EC50: 258.8 and 199.0 nM, respectively) and inhibition of BACE1 in cells (IC50: 136.2 and 98.6 nM, respectively), and showed better activities than the positive controls SCR1693 (a PP2A activator, EC50: 413.9 nM) and LY2811376 (a BACE1 inhibitor, IC50: 260.2 nM). Furthermore, compound 6 showed better therapeutic effects with respect to the reduction of pathological and cognitive impairments in 3 × Tg AD mice than LY2811376. Compound 6 represents the first multitargeted natural product that could activate PP2A and simultaneously inhibit BACE1, which highlights compound 6 as a promising lead compound and a versatile scaffold in AD drug development.

Objective: Alzheimer's disease (AD) is a progressive, fatal brain disorder that would be putting a growing strain on health and social care systems. Present anti-AD agents are limited in their application due to their adverse effects, toxicity, and limited targets in AD pathology. As a result, it is important to develop an AD-fighting compound. Some flavonoids (such as kaempferol, myricetin, quercetin, and syringetin) have been shown to be effective in the treatment of Alzheimer's disease. Methods: We chose 284 flavonoids from the NPACT database for molecular docking studies in order to examine their binding interactions with the Alzheimer target protein CD33. Results: These compounds exhibited significant docking interactions with a variety of targets implicated in the pathogenesis of AD. We chose the top three compounds (Rutin, Morin, and,4,4'-Trihydroxydihydrochalcone) based on the scoring parameter. Conclusion: These compounds exhibited favorable pharmacokinetic properties, indicating that they could be attractive drug candidates for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a complex pathological neurodegenerative disease that seriously threatens human health. Therefore, how to effectively improve and treat AD is an urgent problem. In this study, a novel multitarget derivative based on tacrine (named 9i), which could work simultaneously on more than one pathological target, was used to treat AD model APP/PS1 transgenic mice. After 4 weeks of intragastric administration, cognitive function and synaptic plasticity were significantly improved and β-amyloid (Aβ) plaques that are main pathological hallmarks of AD were decreased in the APP/PS1 mice. On the one hand, 9i inhibited the excessive activation of the Raf/MEK/ERK signaling pathway to alleviate the loss of neurons, which provides a foundation for structural integrity. On the other hand, synaptic associated proteins and the density of synaptic spines were increased in APP/PS1 mice treated with 9i, which provides the basis for the improvement of synaptic plasticity and cognitive impairment. Interestingly, 9i also reduced Aβ plaques in the DG region, which is consistent with previous in vitro experiments showing that 9i inhibited the self-assembly of Aβ fibers, thus protecting neurons from Aβ plaque neurotoxicity. Our results suggest that 9i as a novel compound can effectively improve the cognitive function and the pathological changes of AD in APP/PS1 transgenic mice.

Medicinal plants have curative properties due to the presence of various complex chemical substances of different composition, which are found as secondary metabolites in one or more parts of the plant. The diverse secondary metabolites play an important role in the prevention and cure of various diseases including neurodegenerative diseases like Alzheimer’s disease. Naturally occurring compounds such as flavonoids, polyphenols, alkaloids, and glycosides found in various parts of the plant and/or marine sources may potentially protect neurodegeneration as well as improve memory and cognitive function. Many natural compounds show anti-Alzheimer activity through specific pharmacological mechanisms like targeting β-amyloid, Beta-secretase 1 and Acetylcholinesterase. In this review, we have compiled more than 130 natural products with a broad diversity in the class of compounds, which were isolated from different sources showing anti- Alzheimer properties.

To confront a disease like Alzheimer's disease having complex pathogenesis, development of multitarget-directed ligands has emerged as a promising drug discovery approach. In our endeavor towards the development of multitarget-directed ligands for Alzheimer's disease, a series of indoloquinoxaline derivatives were designed and synthesized. In vitro cholinesterase inhibition studies revealed that all the synthesized compounds exhibited moderate to good cholinesterase inhibitory activity. 6-(6-(Piperidin-1-yl)hexyl)-6

A pair of new enantiomeric neoligans, (±)-neonardochinone A (1) were isolated from Nardostachys chinensis. The structure of 1 was determined by extensive spectroscopic analysis, containing IR, HRESIMS, NMR spectra and single crystal X-ray diffraction. The enantiomeric separation was finished by HPLC on a chiral column. The absolute configurations were assigned via comparison of their calculated and experimental ECD data. The anti-Alzheimer’s disease (AD) activities of 1, 1a, and 1b were also evaluated using the Caenorhabditis elegans AD pathological model, respectively, and 1 had the highest anti-AD activity.

Phytochemical investigation of medicinally important plants has gained great attention, lately. This study aims to investigate the phytochemical constituents of the partitioned extracts (ethyl acetate (AI), dichloromethane (CI) and n-butanol (BI)) derived from the 70% ethanol extract of the rhizomes (RI) of Iris unguicularis Poir. an Algerian-Tunisian endemic plant and to evaluate their biological activities. Seventy constituents of these partitioned extracts were qualitatively characterized by liquid chromatography ion trap time of flight mass spectrometry (LC-MS-IT-TOF) technique. Moreover, quantitative screening of phenolic acids and flavonoids in the studied extracts was accomplished by a previously validated LC-MS/MS method. It was determined that, AI and CI, which were the richest extracts in terms of phytochemical content, showed high antioxidant and antibacterial activities in parallel with their identified constituents, while AI extract was rich in protocatechuic (1080.4 µg analyte/g), 4-OH-benzoic (2218.2 µg/g), syringic (1218.6 µg/g) and pcoumaric (1071.2 µg/g) acids, CI extract has been found to be rich in naringenin (1453.4 µg/g) and ferulic acid (1088.4 µg/g). These results revealed and confirmed the importance of the species and especially the genus rhizomes which have largely been used in folk medicine for the treatment of many diseases. However, all extracts of this endemic plant were inactive at all concentration against acetyl-and butyrylcholinesterase enzymes.

Chromone derivatives possess a spectrum of biological activities. Chromone has been recognized as a privileged structure for new drug invention and development. Substitution pattern of chromone scaffold determines different type of biological activities. The type, number and position of substituents connected to the chromone core play a vital role in determining pharmacological activities. In the present review, we have discussed new chromone derivatives as anticancer, anti-diabetic, antimicrobial, anti-inflammatory, antioxidant and as anti-Alzheimer agents. This review deals with the chromone derivatives prepared by combining chromone molecule with various natural and synthetic pharmacophores and pharmacological activities presented by them. The main aim is to highlight the diversified pharmacological activities exhibited by chromone hybrid molecules during the last eight to ten years.

Background: Considering that AD is multifactorial in nature, novel series of imidazo [2,1-b][1,3,4] thiadiazole derivatives were designed to address the basic factors responsible for the disease. Methods: These compounds were investigated as inhibitors of beta-site APP cleaving enzyme 1, acetylcholinesterase and butyryl cholinesterase. Results: The BACE1 inhibitory results indicated that nitro phenyl substituted derivatives of imidazo [2,1-b][1,3,4] thiadiazole scaffold (R2 = m-NO2) demonstrated superior BACE1 inhibitory activity compared to other substituted moieties. In the BuChE assay, compounds 4h and 4l carrying meta NO2 at R2 of phenyl ring turned out to be potent inhibitors. Conclusion: In conclusion, these novel synthesized derivatives seem to be promising anti-Alzheimer agents.

Traditional Chinese and Japanese medicines have become prime sources of drug discovery and there is a pressing need to investigate the effectiveness of these traditional medicines for modern drug discovery. Recently, among various traditional formulations, studies on Kangen-karyu (Guan-Yuan-Ke-Li), a mixture of six medicinal herbs (Salviae Miltiorrhizae Radix, Cnidii Rhizoma, Paeoniae Radix, Carthami Flos, Aucklandiae Radix, and Cyperi Rhizoma), have been growing to assess its neuroprotective role. This prompted us to undertake a thorough review of various targets of Kangen-karyu regarding its effectiveness against Alzheimer's disease, particularly focusing on cholinesterases, beta-site amyloid precursor protein cleaving enzyme 1, and glycogen synthase kinase 3β. This review provides new insights into Kangen-karyu medication as a prospective anti-Alzheimer's medication and indicates the need for in-depth in vivo investigation in the future.

Background: Coumarins exhibit a plethora of biological activities, e.g. antiinflammatory and anti-tumor. Molecular hybridization technique has been implemented in the design of novel coumarin hybrids with several bioactive groups in order to obtain molecules with better pharmacological activity and improved pharmacokinetic profile. Objective: Therefore, we tried to gather as many as possible biologically active coumarin hybrids referred in the literature till now, to delineate the structural characteristics in relation to the activities and to have a survey that might help the medicinal chemists to design new coumarin hybrids with drug-likeness and varied bioactivities. Results: The biological activities of the hybrids in most of the cases were found to be different from the biological activities presented by the parent coumarins. The results showed that the hybrid molecules are more potent compared to the standard drugs used in the evaluation experiments. Conclusion: Conjugation of coumarin with varied pharmacophore groups/druglike molecules responsible for different biological activities led to many novel hybrid molecules, with a multitarget behavior and improved pharmacokinetic properties.

Inhibition of acetylcholinesterase (AChE) is a promising strategy for the management of Alzheimer’s disease (AD). Prolyl endopeptidase (PEP) is a post-proline cleaving enzyme that plays an importan...

In search of suitable therapy for the management of Alzheimer’s disease, this study was designed to evaluate metal complexes against its biochemical targets. Zinc metal carboxylates (AAZ1–AAZ6) wer...

Semi-empirical calculations on the torsion potential for dihedral angle of rivastigmine linking NAP and Carbamyle moieties consistently show regions of several discontinuities and a cusp indicating molecular instability and eventual break-up of rivastigmine observed in the X-ray structure. The phenomena can be explained both by definition of large classical force or quantum nature of chemical bond break-up. Also, to better understand the molecular properties and quantum energetics of the inhibitor molecules, we have performed several ab initio based calculations on all four inhibitors at equilibrium geometry, in ground state and gas phase using the density functional theory level wB97X/6-31G* and HF/6-31G*. A number of properties like computational vibrational (IR), Raman and nuclear magnetic resonance (NMR) spectra as well as HOMO and LUMO orbital energies at optimized geometries have been computed by SPARTAN16 and Gaussian16 utilities. Also, the thermodynamic and QSAR properties of the inhibitors have been assessed and compared by a number of different semi-quantum, Hartree-Fock and density functional methods. The theoretical NMR and IR spectra have been benchmarked against experimental spectrum to compare and assess suitability of the computational methodologies and basis set levels for the calculations.Communicated by Ramaswamy H. Sarma.

Eupulcherol A (1), a novel triterpenoid with an unprecedented carbon skeleton, was isolated from Euphorbia pulcherrima. Its structure was determined by comprehensive analysis of spectroscopic data, including HRESIMS and 1D and 2D NMR, and the absolute configuration was defined by single crystal X-ray diffraction analysis. Biological studies showed that compound 1 possessed anti-Alzheimer's disease (AD) bioactivity, which could delay paralysis of transgenic AD Caenorhabditis elegans. A plausible biogenetic pathway for eupulcherol A (1) was also proposed.

Multi-target drugs can better address the cascade of events involved in oxidative stress and the reduction in cholinergic transmission that occur in Alzheimer’s disease than cholinesterase inhibitors alone. We synthesised a series of 3-arylbenzofuranone derivatives and evaluated their antioxidant activity, cholinesterase inhibitory activity, and monoamine oxidase inhibitory activity. 3-Arylbenzofuranone compounds exhibit good antioxidant activity as well as selective acetylcholinesterase inhibitory activity. The IC50 value of anti-acetylcholinesterase inhibition of Compound 20 (0.089 ± 0.01 μM) is similar to the positive drug donepezil (0.059 ± 0.003 μM). According to the experimental results, Compounds 7, 13 show a certain effect in the in vitro evaluation performed and have the potential as drug candidates for the treatment of Alzheimer’s disease.

A series of multi-target directed edaravone derivatives bearing N-benzyl pyridinium moieties were designed and synthesised. Edaravone is a potent antioxidant with significant neuroprotective effects and N-benzyl pyridinium has previously exhibited positive results as part of a dual-site binding, peripheral anionic site (PAS) and catalytic anionic site (CAS), acetylcholinesterase (AChE) inhibitor. The designed edaravone-N-benzyl pyridinium hybrid compounds were docked within the AChE active site. The results indicated interactions with conserved amino acids (Trp279 in PAS and Trp84 in CAS), suggesting good dual-site inhibitory activity. Significant in vitro AChE inhibitory activities were observed for selected compounds (IC50: 1.2–4.6 µM) with limited butyrylcholinesterase inhibitory activity (IC50’s >160 µM), indicating excellent selectivity towards AChE (SI: 46 – >278). The compounds also showed considerable antioxidant ability, similar to edaravone. In silico studies indicated that these compounds should cross the blood–brain barrier, making them promising lead molecules in the development of anti-Alzheimer’s agents.

Context: Alzheimer’s disease (AD) is a chronic neurodegenerative disease that originates from central nervous system lesions or recessions. Current estimates suggest that this disease affects over 35 million people worldwide. However, lacking effective drugs is the biggest handicap in treating AD. In traditional Chinese medicine (TCM), Polygala tenuifolia Willd. (Polygalaceae) is generally used to treat insomnia, memory dysfunction and neurasthenia. Objective: This review article explores the role of P. tenuifolia and its active components in anti-Alzheimer’s disease. Methods: Literature for the last ten years was obtained through a search on PubMed, SciFinder, CNKI, Google Scholar, Web of Science, Science Direct and China Knowledge Resource Integrated with the following keywords: Polygala tenuifolia, polygalasaponin XXXII (PGS 32), tenuifolin, polygalacic acid, senegenin, tenuigenin, Alzheimer’s disease. Results: Polygala tenuifolia and its active components have multiplex neuroprotective potential associated with AD, such as anti-Aβ aggregation, anti-Tau protein, anti-inflammation, antioxidant, anti-neuronal apoptosis, enhancing central cholinergic system and promote neuronal proliferation. Conclusions: Polygala tenuifolia and its active components exhibit multiple neuroprotective effects. Hence, P. tenuifolia is a potential drug against Alzheimer’s disease, especially in terms of prevention.

Coffee is among the most commonly consumed beverage all over the world. Studies have increasingly suggested caffeine and coffee as effective therapeutic interventions against Alzheimer's disease (AD). We have therefore utilized the aluminum chloride rat model for AD to compare the influence of moderately caffeinated (Arabian) and decaffeinated (Date palm seed) coffee on cognitive impairment and pathological events in AD. AD rats given Arabian or Date palm seed coffee were protected against memory impairment and had lower serum levels of the abnormal protein (amyloid-beta; Aβ1-42), the central pathogenic contributor to AD, and transforming growth factor-beta (TGF-β). Interestingly, Date palm seed (decaffeinated) coffee seems to provide more pronounced protection against AD than Arabian (moderately caffeinated) coffee as evidenced by the greater decrease in serum Aβ levels. These results suggest a surprising therapeutic potential of moderate caffeine intake in Arabian coffee to ameliorate AD through decreasing serum Aβ levels. However, Date palm seed (decaffeinated) coffee, rich in flavonoids, appears to provide a better AD-modifying ability through a direct reduction of Aβ production. PRACTICAL APPLICATIONS: Consumption of moderately caffeinated Arabian coffee attenuated AD-induced cognitive impairment via its anti-amyloidogenic potential, decreasing Aβ levels. Moreover, intake of decaffeinated Date seed extract, rich in flavonoids, exerted a superior anti-AD potential through a direct reduction of Aβ production. Both of them were also safe and maintained hepatic and renal functions in a rat model of AlCl3 -induced AD. Further clinical studies are warranted to confirm current results and to recommend the regular drinking of Arabian coffee or Date seed extract as a protective approach to delay AD progression in vulnerable individuals or in early disease stages.

Natural bioactive compounds of Marine origin have attracted the attention of many biologists and chemists in the world over for the last five decades because it has proven to be a rich source of structurally diverse and complex compounds exhibiting numerous interesting biological functions. At present, many research findings have provided insight into biological activities of marine natural compounds such as antioxidant- and anti-cholinesterase activity and neuroprotective effects on neurodegenerative diseases, viz. Alzheimer’s and Parkinson’s. The main pathological hallmarks of AD is the formation senile plaques, neurofibrillary tangles and the most incredible physiological and biochemical changes are reduction in acetylcholine (ACh) levels in the hippocampus and cortex of the brain and loss of memory, decaying language etc. Present study is focused on to enhance the acetylcholine levels and subsequently to prevent the formation of Senile Plaques and Neuro Fibrillary Tangles in tau protein responsible for Alzheimer’s disease by using natural bioactive compound Squalene. Computational Biology and Bio-informatics have the potential not only to speed up the drug discovery process but reduces the costs. Further, they also change the way drugs are designed by using Docking Techniques employed to dock a set of marine bioactive compounds within the active site region of 1B41 & 2V17 by using Auto Dock vina. The docking simulation clearly predicted the interaction and highest binding energy docking scores against Squalene, analogues were retrieved from ZINC database i.e. ZINC 0118 (-8.9) and ZINC 0142 (-8.3) for 4B05 & 2V17 enzymes respectively. Further, we Studied visualization aspects in PyMol and also satisfied the biological activity predictions like OSIRIS, Molinspiration and PASS Prediction results by inhibiting the activity of Tau and Acetyl Cholinesterase receptors in AD.

Background: Bacopa monnieri (Brahmi; family Scrophulariaceae) is a well-known plant known for its nootropic activity. Delivery of Bacosides (an active constituent) is limited at the site of action owing to the existence of the Blood-Brain Barrier (BBB). In order to take the Bacoside- Rich Extract (BRE) across BBB, formulated solid lipid nanoparticles (SLNs) were used. Objective: The objective of this work was to evaluate the pharmacokinetic and pharmacodynamic behavior (in vivo potential) of the prepared SLNs containing BRE in comparison to BRE alone for the treatment of Alzheimer’s disease. Methods: Swiss albino male mice (25-30 gm) were used for the study. The pharmacokinetic, as well as pharmacodynamic evaluation of formulated SLNs, were performed in comparison to BRE in a scopolamine-induced amnesia model. Results: BRE-loaded SLNs were found to be significantly more effective than BRE in alleviating neurodegeneration. The pharmacokinetic study revealed the improved bioavailability of prepared SLNs with the potential of sustaining the drug release in mice for an extended period of time. Conclusion: The results demonstrated that the SLNs can be considered as a potential delivery system for taking BRE across the BBB to treat Alzheimer’s disease.

The inhibition of glutaminyl cyclase (QC) may provide a promising strategy for the treatment of early Alzheimer's disease (AD) by reducing the amount of the toxic pyroform of β-amyloid (AβΝ3pE) in the brains of AD patients. In this work, we identified potent QC inhibitors with subnanomolar IC50 values that were up to 290-fold higher than that of PQ912, which is currently being tested in Phase II clinical trials. Among the tested compounds, the cyclopentylmethyl derivative (214) exhibited the most potent in vitro activity (IC50 = 0.1 nM), while benzimidazole (227) showed the most promising in vivo efficacy, selectivity and druggable profile. 227 significantly reduced the concentration of pyroform Aβ and total Aβ in the brain of an AD animal model and improved the alternation behavior of mice during Y-maze tests. The crystal structure of human QC (hQC) in complex with 214 indicated tight binding at the active site, supporting that the specific inhibition of QC results in potent in vitro and in vivo activity. Considering the recent clinical success of donanemab, which targets AβΝ3pE, small molecule-based QC inhibitors may also provide potential therapeutic options for early-stage AD treatment.

Alzheimer’s disease (AD) is an irreversible and progressive brain disorder that slowly destroys memory and thinking skills, and, eventually, the ability to perform simple tasks. As the aging population continues to increase exponentially, AD has become a big concern for society. Therefore, neuroprotective compounds are in the spotlight, as a means to tackle this problem. On the other hand, since it is believed—in many cultures—that marine organisms in an individual diet cannot only improve brain functioning, but also slow down its dysfunction, many researchers have focused on identifying neuroprotective compounds from marine resources. The fact that the marine environment is a rich source of structurally unique and biologically and pharmacologically active compounds, with unprecedented mechanisms of action, marine macroorganisms, such as tunicates, corals, sponges, algae, as well as microorganisms, such as marine-derived bacteria, actinomycetes, and fungi, have been the target sources of these compounds. Therefore, this literature review summarizes and categorizes various classes of marine-derived compounds that are able to inhibit key enzymes involved in AD, including acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), β-secretase (BACE-1), and different kinases, together with the related pathways involved in the pathogenesis of AD. The compounds discussed herein are emerging as promising anti-AD activities for further in-depth in vitro and in vivo investigations, to gain more insight of their mechanisms of action and for the development of potential anti-AD drug leads.

Natural dyes recognized as carotenoids have found application in health care system due to their wide biological activities, high safety margins and lower cost. Crocetin, a carotenoid constituent of saffron has shown wide range of pharmacological applications due to its significant antioxidant properties. It is used as antifungal, antimicrobial and antiallergic agent. Crocetin has shown significant potential as an anti- tumor agent in animal models and cell culture systems. Current review has shown crocetin’s multispectrum pharmacological benefits for the treatment of various chronic diseases such as cancer, diabetes, parkinson’s and alzheimer’s disease. This review focus on various studies done on crocetin explaining its broa d spectrum pharmacological activities. In addition, this review will also focus on the pharmacokinetic studies of crocetin on human and animals. Crocetin is a highly potent molecule because of its strong antioxidant properties. In the near future, increasing its bioavailability using novel drug delivery methods having minimum side effects will get this promising natural molecule to the forefront of therapy for the treatment of various chronic human diseases like cancer, diabetes, parkinson’s and alzheimer’s disease.

Objective: The aim was to assess the effect of anti-Alzheimer’s activity of the alcoholic extract of Costus pictus D. Don Leaves in Alzheimer induce Wistar albino rats. Methods: In the present study, the efficacy of an Extract of Costus pictus D. Don (ECPDD) was evaluated against scopolamine-induced Alzheimer in the Wistar albino rat. Donepezil at a dose of 2.5 mg/kg, ECPDD was given in rat at a dose of 100 mg/kg body weight, 150 mg/kg body weight, and 200 mg/kg body weight. Anti-Alzheimer activity was assessed by victimization novel object recognition test, elevated plus maze, and Y-maze. And by biochemical test like neurotransmitter esterase activity, catalase activity, malonyldialdehyd and glutathione assays. Results: Results showed that extracts treatment prevents Alzheimer and increases the level of acetylcholine, catalase, glutathione peroxidase, and phytochemical studies identified the presence of flavonoid and alkaloid in the ECPDD. Conclusion: According to the results, it was concluded that the leave of C. pictus D. Don has significant anti-Alzheimer activity due to the presence of potent antioxidants such as flavonoid and anticholinesterase enzyme present in alkaloids.

Here we present a novel life-long whole-population study, which enabled us to predict a diet that, in terms of macronutrient proportions, may be prophylactic against Alzheimer’s Disease (AD). The method is based on the existence of oscillations in the correlation between historical per capita personal income (PCPI) and age-adjusted death rates (AADR) for AD for each state of the USA in 2005. These oscillations can be explained by changing proportions of macronutrients in the average American diet between 1929 and 2005. We assumed that reducing future correlation of PCPI with AADR will reduce the population’s susceptibility to AD. Based on the results of fitting macronutrient availabilities to the variability of Roriginal, using Generalized Additive Models (GAM) analysis, we constructed four “Calculator” equations. The Calculator allowed for prediction of an optimal diet characterized by low correlation of PCPI with AADR (Rpredicted) and minimum energy difference from the historical average macronutrient consumption for each corresponding period of life. We predict that protein consumption should be reduced by half in early middle age and late middle age, whereas in late age it should increase. Our predictions are in line with results on humans and simpler organisms in the context of prolonging life.

The most common type of dementia found in the elderly population is Alzheimer’s disease. The disease not only impacts the patients and their families but also the society therefore, the main focus of researchers is to search new bioactive materials for treating AD. The marine environment is a rich source of functional ingredients and to date, we can find sufficient research relating to anti- Alzheimer’s compounds isolated from marine environment. Therefore, this review focuses on the anti- Alzheimer’s material from marine bio-resources and then expounds on the anti-Alzheimer’s compounds from marine seaweed, marine animal and marine microorganisms. Moreover, because of the complexity of the disease, different hypothesizes have been elaborated and active compounds have been isolated to inhibit different stages of pathophysiological mechanisms. Sulfated polysaccharides, glycoprotein, and enzymatic hydrolysates from marine seaweeds, peptides, dietary omega-3 polyunsaturated fatty acids and skeletal polysaccharide from marine animals and secondary metabolites from marine microorganism are summarized in this review under the anti-Alzheimer’s compounds from the marine.

The cure from Alzheimer's disease is a challenging mission. Acetylcholinesterase enzyme (AChE) inhibitors, including tacrine, are considered the most important line for Alzheimer's therapy. In the current study, we aimed at designing and synthesizing new thienopyridine-tacrine analogues. The molecular structures of the synthesized compounds were illustrated by spectroscopic and elemental analysis. These compounds have been screened for their in vivo brain acetyl cholinesterase inhibition activities. The majority of the tested compounds exhibited inhibitory activity towards AChE. The IC 50 for the most promising members was determined in vitro . Interestingly, compound 11a displayed the best profile with IC 50 of about 172 nM.

Virtual screening emerged as an important tool in our quest to access successful CNS medicaments for treating Alzheimer's disease. The computational techniques applied in this screening are central nervous system multiparameter optimization (CNS MPO), golden triangle rule, structure activity/property relationships (SAR/SPR), Drug-likeness properties, and lipophilicity indices. These techniques offer the ability to guide drug design and selection to a quickly identify the compounds from a class of acetylcholinesterase inhibitors being pyridazine derivatives, with desirable drug-like attributes.

The multifaceted nature of Alzheimer's disease (AD) demands treatment with multitarget-directed ligands (MTDLs) to confront the key pathological aberrations. A novel series of triazinoindole derivatives were designed and synthesized. In vitro studies revealed that all the compounds showed moderate to good anticholinesterase activity; the most active compound