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Assessment of the Blood-Brain Barrier Permeability of Potential Neuroprotective Aurones in Parallel Artificial Membrane Permeability Assay and Porcine Brain Endothelial Cell Models

Liew KF, Hanapi NA, Chan KL, Yusof SR, Lee CY

J Pharm Sci, 2017 02;106(2):502-510.
PMID: 27855959 DOI: 10.1016/j.xphs.2016.10.006

Previously, several aurone derivatives were identified with promising neuroprotective activities. In developing these compounds to target the central nervous system (CNS), an assessment of their blood-brain barrier (BBB) permeability was performed using in vitro BBB models: parallel artificial membrane permeability assay-BBB which measures passive permeability and primary porcine brain endothelial cell model which enables determination of the involvement of active transport mechanism. Parallel artificial membrane permeability assay-BBB identified most compounds with high passive permeability, with 3 aurones having exceptional Pevalues highlighting the importance of basic amine moieties and optimal lipophilicity for good passive permeability. Bidirectional permeability assays with porcine brain endothelial cell showed a significant net influx permeation of the aurones indicating a facilitated uptake mechanism in contrast to donepezil, a CNS drug included in the evaluation which only displayed passive permeation. From pH-dependent permeability assay coupled with data analysis using pCEL-X software, intrinsic transcellular permeability (Po) of a representative aurone 4-3 was determined, considering factors such as the aqueous boundary layer that may hinder accurate in vitro to in vivo correlation. The Po value determined supported the in vivo feasibility of the aurone as a CNS-active compound.

Matched MeSH terms: Neuroprotective Agents/chemistry*
Fulltext Neuroprotective Strategies for Neurological Disorders by Natural Products: An update

Rehman MU, Wali AF, Ahmad A, Shakeel S, Rasool S, Ali R, et al.

Curr Neuropharmacol, 2019;17(3):247-267.
PMID: 30207234 DOI: 10.2174/1570159X16666180911124605

Nature has bestowed mankind with surplus resources (natural products) on land and water. Natural products have a significant role in the prevention of disease and boosting of health in humans and animals. These natural products have been experimentally documented to possess various biological properties such as antioxidant, anti-inflammatory and anti-apoptotic activities. In vitro and in vivo studies have further established the usefulness of natural products in various preclinical models of neurodegenerative disorders. Natural products include phytoconstituents, like polyphenolic antioxidants, found in herbs, fruits, nuts, vegetables and also in marine and freshwater flora. These phytoconstituents may potentially suppress neurodegeneration and improve memory as well as cognitive functions of the brain. Also, they are known to play a pivotal role in the prevention and cure of different neurodegenerative diseases, such as Alzheimer's disease, epilepsy, Parkinson's disease and other neuronal disorders. The large-scale neuro-pharmacological activities of natural products have been documented due to the result of either the inhibition of inflammatory processes, or the up-regulation of various cell survival proteins or a combination of both. Due to the scarcity of human studies on neuroprotective effects of natural products, this review focuses on the various established activities of natural products in in vitro and in vivo preclinical models, and their potential neuro-therapeutic applications using the available knowledge in the literature.

Matched MeSH terms: Neuroprotective Agents/chemistry
Fulltext Neuroprotective Potential of Secondary Metabolites from Melicope lunu-ankenda (Rutaceae)

Abdulwanis Mohamed Z, Mohamed Eliaser E, Mazzon E, Rollin P, Cheng Lian Ee G, Abdull Razis AF

Molecules, 2019 Aug 27;24(17).
PMID: 31461914 DOI: 10.3390/molecules24173109

Plant natural compounds have great potential as alternative medicines for preventing and treating diseases. Melicope lunu-ankenda is one Melicope species (family Rutaceae), which is widely used in traditional medicine, consumed as a salad and a food seasoning. Consumption of different parts of this plant has been reported to exert different biological activities such as antioxidant and anti-inflammatory qualities, resulting in a protective effect against several health disorders including neurodegenerative diseases. Various secondary metabolites such as phenolic acid derivatives, flavonoids, coumarins and alkaloids, isolated from the M. lunu-ankenda plant, were demonstrated to have neuroprotective activities and also exert many other beneficial biological effects. A number of studies have revealed different neuroprotective mechanisms for these secondary metabolites. This review summarizes the most significant and recent studies for neuroprotective activity of M. lunu-ankenda major secondary metabolites in neurodegenerative diseases.

Matched MeSH terms: Neuroprotective Agents/chemistry
Probing the anti-Aβ42 aggregation and protective effects of prenylated xanthone against Aβ42-induced toxicity in transgenic Caenorhabditis elegans model

Thew HY, Boon Keat K, Tan YC, Ong YS, Parat MO, Murugaiyah V, et al.

Chem Biol Interact, 2024 May 01;394:110978.
PMID: 38552766 DOI: 10.1016/j.cbi.2024.110978

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) protein aggregates, leading to synaptic dysfunction and neuronal cell death. In this study, we used a comprehensive approach encompassing in vitro assays, computational analyses, and an in vivo Caenorhabditis elegans model to evaluate the inhibitory effects of various xanthones, focusing on Garcinone D (GD), on Aβ42 oligomer formation. Dot blot analysis revealed concentration-dependent responses among xanthones, with GD consistently inhibiting Aβ42 oligomer formation at low concentrations (0.1 and 0.5 μM, inhibitions of 84.66 ± 2.25% and 85.06 ± 6.57%, respectively). Molecular docking and dynamics simulations provided insights into the molecular interactions between xanthones and Aβ42, highlighting the disruption of key residues involved in Aβ42 aggregation. The neuroprotective potential of GD was established using transgenic C. elegans GMC101, with substantial delays in paralysis reported at higher concentrations. Our findings show that GD is a potent suppressor of Aβ42 oligomer formation, suggesting its potential as a therapeutic candidate for AD. The concentration-dependent effects observed in both in vitro and in vivo models underscore the need for nuanced dose-response assessments. These findings contribute novel insights into the therapeutic landscape of xanthones against AD, emphasizing the multifaceted potential of GD for further translational endeavors in neurodegenerative disorder research.

Matched MeSH terms: Neuroprotective Agents/chemistry
Fulltext Neuroprotective Potential of Chrysin: Mechanistic Insights and Therapeutic Potential for Neurological Disorders

Mishra A, Mishra PS, Bandopadhyay R, Khurana N, Angelopoulou E, Paudel YN, et al.

Molecules, 2021 Oct 26;26(21).
PMID: 34770864 DOI: 10.3390/molecules26216456

Chrysin, a herbal bioactive molecule, exerts a plethora of pharmacological effects, including anti-oxidant, anti-inflammatory, neuroprotective, and anti-cancer. A growing body of evidence has highlighted the emerging role of chrysin in a variety of neurological disorders, including Alzheimer's and Parkinson's disease, epilepsy, multiple sclerosis, ischemic stroke, traumatic brain injury, and brain tumors. Based on the results of recent pre-clinical studies and evidence from studies in humans, this review is focused on the molecular mechanisms underlying the neuroprotective effects of chrysin in different neurological diseases. In addition, the potential challenges, and opportunities of chrysin's inclusion in the neurotherapeutics repertoire are critically discussed.

Matched MeSH terms: Neuroprotective Agents/chemistry
Neuroprotective effect from stem bark extracts of Knema laurina against H₂O₂- and Aβ(1-42)-induced cell death in human SH-SY5Y cells

Ismail N, Akhtar MN, Ismail M, Zareen S, Shah SA, Lajis NH, et al.

Nat Prod Res, 2015;29(16):1571-4.
PMID: 25471591 DOI: 10.1080/14786419.2014.985676

The stem bark extracts of Knema laurina inhibited the hydrogen peroxide (H2O2)- and aggregated amyloid β-peptide 1-42 length (Aβ(1-42))-induced cell death in differentiated SH-SY5Y cells. Exposure of 250 μM H2O2 or 20 μM Aβ(1-42) to the cells for 24 h reduced 50% of cell viability. Pretreatment of cells with ethyl acetate extract (EAE) or n-butanol extract (BE) at 300 μg/mL and then exposure to H2O2 protected the cells against the neurotoxic effects of H2O2. Besides, methanolic extract (ME) at 1 and 10 μg/mL exerted neuroprotective effect on Aβ(1-42)-induced toxicity to the cells. These results showed that EAE, BE and ME exhibited neuroprotective activities against H2O2- and Aβ(1-42)-induced cell death. Flavonoids (3-6) and β-sitosterol glucoside (8) were isolated from the EAE. Compound 1 was isolated from hexane extract, and compounds 2 and 7 were isolated from dichloromethane extract. All these observations provide the possible evidence for contribution in the neuroprotective effects.

Matched MeSH terms: Neuroprotective Agents/chemistry*
Fulltext RP-UHPLC-MS Chemical Profiling, Biological and In Silico Docking Studies to Unravel the Therapeutic Potential of Heliotropium crispum Desf. as a Novel Source of Neuroprotective Bioactive Compounds

Arshad A, Ahemad S, Saleem H, Saleem M, Zengin G, Abdallah HH, et al.

Biomolecules, 2021 01 04;11(1).
PMID: 33406643 DOI: 10.3390/biom11010053

Heliotropium is one of the most important plant genera to have conventional folklore importance, and hence is a potential source of bioactive compounds. Thus, the present study was designed to explore the therapeutic potential of Heliotropium crispum Desf., a relatively under-explored medicinal plant species. Methanolic extracts prepared from a whole plant of H. crispum were studied for phytochemical composition and possible in vitro and in silico biological properties. Antioxidant potential was assessed via six different assays, and enzyme inhibition potential against key clinical enzymes involved in neurodegenerative diseases (acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)), diabetes (α-amylase and α-glucosidase), and skin problems (tyrosinase) was assayed. Phytochemical composition was established via determination of the total bioactive contents and reverse phase ultra-high performance liquid chromatography mass spectrometry (RP-UHPLC-MS) analysis. Chemical profiling revealed the tentative presence of 50 secondary metabolites. The plant extract exhibited significant inhibition against AChE and BChE enzymes, with values of 3.80 and 3.44 mg GALAE/g extract, respectively. Further, the extract displayed considerable free radical scavenging activity against DPPH and ABTS radicals, with potential values of 43.19 and 41.80 mg TE/g extract, respectively. In addition, the selected compounds were then docked against the tested enzymes, which have shown high inhibition affinity. To conclude, H. crispum was found to harbor bioactive compounds and showed potent biological activities which could be further explored for potential uses in nutraceutical and pharmaceutical industries, particularly as a neuroprotective agent.

Matched MeSH terms: Neuroprotective Agents/chemistry*
Hybrid molecules based on 1,3,5-triazine as potential therapeutics: A focused review

Prasher P, Sharma M, Aljabali AAA, Gupta G, Negi P, Kapoor DN, et al.

Drug Dev Res, 2020 11;81(7):837-858.
PMID: 32579723 DOI: 10.1002/ddr.21704

Majority of the representative drugs customarily interact with multiple targets manifesting unintended side effects. In addition, drug resistance and over expression of the cellular efflux-pumps render certain classes of drugs ineffective. With only a few innovative formulations in development, it is necessary to identify pharmacophores and novel strategies for creating new drugs. The conjugation of dissimilar pharmacophoric moieties to design hybrid molecules with an attractive therapeutic profile is an emerging paradigm in the contemporary drug development regime. The recent decade witnessed the remarkable biological potential of 1,3,5-triazine framework in the development of various chemotherapeutics. The appending of the 1,3,5-triazine nucleus to biologically relevant moieties has delivered exciting results. The present review focuses on 1,3,5-triazine based hybrid molecules in the development of pharmaceuticals.

Matched MeSH terms: Neuroprotective Agents/chemistry
Synthesis of α, β-unsaturated carbonyl based compounds as acetylcholinesterase and butyrylcholinesterase inhibitors: characterization, molecular modeling, QSAR studies and effect against amyloid β-induced cytotoxicity

Bukhari SN, Jantan I, Masand VH, Mahajan DT, Sher M, Naeem-ul-Hassan M, et al.

Eur J Med Chem, 2014 Aug 18;83:355-65.
PMID: 24980117 DOI: 10.1016/j.ejmech.2014.06.034

A series of novel carbonyl compounds was synthesized by a simple, eco-friendly and efficient method. These compounds were screened for anti-oxidant activity, in vitro cytotoxicity and for inhibitory activity for acetylcholinesterase and butyrylcholinesterase. The effect of these compounds against amyloid β-induced cytotoxicity was also investigated. Among them, compound 14 exhibited strong free radical scavenging activity (18.39 μM) while six compounds (1, 3, 4, 13, 14, and 19) were found to be the most protective against Aβ-induced neuronal cell death in PC12 cells. Compounds 4 and 14, containing N-methyl-4-piperidone linker, showed high acetylcholinesterase inhibitory activity as compared to reference drug donepezil. Molecular docking and QSAR (Quantitative Structure-Activity Relationship) studies were also carried out to determine the structural features that are responsible for the acetylcholinesterase and butyrylcholinesterase inhibitory activity.

Matched MeSH terms: Neuroprotective Agents/chemistry
Synthetic Curcumin Analogs as Inhibitors of β -Amyloid Peptide Aggregation: Potential Therapeutic and Diagnostic Agents for Alzheimer's Disease

Bukhari SN, Jantan I

Mini Rev Med Chem, 2015;15(13):1110-21.
PMID: 26420724

There is a crucial need to develop new effective drugs for Alzheimer's disease (AD) as the currently available AD treatments provide only momentary and incomplete symptomatic relief. Amongst natural products, curcumin, a major constituent of turmeric, has been intensively investigated for its neuroprotective effect against β-amyloid (Aβ)-induced toxicity in cultured neuronal cells. The ability of curcumin to attach to Aβ peptide and prevent its accumulation is attributed to its three structural characteristics such as the presence of two aromatic end groups and their co-planarity, the length and rigidity of the linker region and the substitution conformation of these aromatics. However, curcumin failed to reach adequate brain levels after oral absorption in AD clinical trials due to its low water solubility and poor oral bioavailability. A number of new curcumin analogs that mimic the active site of the compound along with analogs that mimic the curcumin anti-amyloid effect combined with anticholinesterase effect have been developed to enhance the bioavailability, pharmacokinetics, water solubility, stability at physiological conditions and delivery of curcumin. In this article, we have summarized all reported synthetic analogs of curcumin showing effects on β-amyloid and discussed their potential as therapeutic and diagnostic agents for AD.

Matched MeSH terms: Neuroprotective Agents/chemistry*
Biological evaluation of synthetic α,β-unsaturated carbonyl based cyclohexanone derivatives as neuroprotective novel inhibitors of acetylcholinesterase, butyrylcholinesterase and amyloid-β aggregation

Zha GF, Zhang CP, Qin HL, Jantan I, Sher M, Amjad MW, et al.

Bioorg Med Chem, 2016 05 15;24(10):2352-9.
PMID: 27083471 DOI: 10.1016/j.bmc.2016.04.015

A series of new α,β-unsaturated carbonyl-based cyclohexanone derivatives was synthesized by simple condensation method and all compounds were characterized by using various spectroscopic techniques. New compounds were evaluated for their effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). These compounds were also screened for in vitro cytotoxicity and for inhibitory activity for self-induced Aβ1-42 aggregation. The effect of these compounds against amyloid β-induced cytotoxicity was also investigated. The findings of in vitro experiment revealed that most of these compounds exhibited potent inhibitory activity against AChE and self-induced Aβ1-42 aggregation. The compound 3o exhibited best AChE (IC50=0.037μM) inhibitory potential. Furthermore, compound 3o disassembled the Aβ fibrils produced by self-induced Aβ aggregation by 76.6%. Compounds containing N-methyl-4-piperidone linker, showed high acetylcholinesterase and self-induced Aβ aggregation inhibitory activities as compared to reference drug donepezil. The pre-treatment of cells with synthetic compounds protected them against Aβ-induced cell death by up to 92%. Collectively, these findings suggest that some compounds from this series have potential to be promising multifunctional agents for AD treatment and our study suggest the cyclohexanone derivatives as promising new inhibitors for AChE and BuChE, potentially useful to treat neurodegenerative diseases.

Matched MeSH terms: Neuroprotective Agents/chemistry*
Rutin, a bioflavonoid antioxidant protects rat pheochromocytoma (PC-12) cells against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity

Magalingam KB, Radhakrishnan A, Haleagrahara N

Int J Mol Med, 2013 Jul;32(1):235-40.
PMID: 23670213 DOI: 10.3892/ijmm.2013.1375

Free radicals are widely known to be the major cause of human diseases such as neurodegenerative diseases, cancer, allergy and autoimmune diseases. Human cells are equipped with a powerful natural antioxidant enzyme network. However, antioxidants, particularly those originating from natural sources such as fruits and vegetables, are still considered essential. Rutin, a quercetin glycoside, has been proven to possess antioxidant potential. However, the neuroprotective effect of rutin in pheochromocytoma (PC-12) cells has not been studied extensively. Therefore, the present study was designed to establish the neuroprotective role of rutin as well as to elucidate the antioxidant mechanism of rutin in 6-hydroxydopamine (6-OHDA)-induced toxicity in PC-12 neuronal cells. PC-12 cells were pretreated with different concentrations of rutin for 4, 8 and 12 h and subsequently incubated with 6-OHDA for 24 h to induce oxidative stress. A significant cytoprotective activity was observed in rutin pretreated cells in a dose-dependent manner. Furthermore, there was marked activation of antioxidant enzymes including superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), and total glutathione (GSH) in rutin pretreated cells compared to cells incubated with 6-OHDA alone. Rutin significantly reduced lipid peroxidation in 6-OHDA-induced PC-12 cells. On the basis of these observations, it was concluded that the bioflavonoid rutin inhibited 6-OHDA-induced neurotoxicity in PC-12 cells by improving antioxidant enzyme levels and inhibiting lipid peroxidation.

Matched MeSH terms: Neuroprotective Agents/chemistry
Danshen (Salvia miltiorrhiza) water extract shows potential neuroprotective effects in Caenorhabditis elegans

Yuen CW, Murugaiyah V, Najimudin N, Azzam G

J Ethnopharmacol, 2021 Feb 10;266:113418.
PMID: 32991971 DOI: 10.1016/j.jep.2020.113418

ETHNOPHARMACOLOGICAL RELEVANCE: Danshen, is a traditional Chinese medicine obtained from the dried root and rhizome of Salvia miltiorrhiza Bunge. It is known to be used for neurological disorder including for Alzheimer's disease (AD). This study uncovers the effect of Danshen water extract on the Alzheimer's disease model of C.elegans.
MATERIAL AND METHODS: The composition of Danshen water extract was determined using (High Performance Liquid Chromatography (HPLC). Then Thioflavin T assay was used to determined if Danshen water extract could prevent the aggregation of amyloid-β peptide (Aβ). Alzheimer's disease C.elegans model was used to determine the effect of Danshen water extract. Finally, the reactive oxygen species (ROS) was determined using the 2,7-dichlorofuorescein diacetate method.
RESULTS: In this study, we found that standardized Danshen water extract that contains danshensu (1.26%), salvianolic acid A (0.35%) and salvianolic acid B (2.21%) are able to bind directly to Aβ and prevents it from aggregating. The IC50 for the inhibition of Aβ aggregation by Danshen water extract was 0.5 mg/ml. In the AD model of C.elegans, Danshen water extract managed to alleviates the paralysis phenotype. Furthermore, the administration of Danshen water extract displayed antioxidant properties toward the Aβ-induced oxidative stress.
CONCLUSIONS: AD is a widespread neurodegenerative disease attributed to the accumulation of extracellular plaques comprising Aβ. Danshen water extract could significantly reduce the progress of paralysis in the AD model of C. elegans, showing promising results with its antioxidant properties. It can be concluded that Danshen water extract could potentially serve as a therapeutic for AD.

Matched MeSH terms: Neuroprotective Agents/chemistry
Fulltext Potential of Naturally Derived Alkaloids as Multi-Targeted Therapeutic Agents for Neurodegenerative Diseases

Kong YR, Tay KC, Su YX, Wong CK, Tan WN, Khaw KY

Molecules, 2021 Jan 30;26(3).
PMID: 33573300 DOI: 10.3390/molecules26030728

Alkaloids are a class of secondary metabolites that can be derived from plants, fungi and marine sponges. They are widely known as a continuous source of medicine for the management of chronic disease including cancer, diabetes and neurodegenerative diseases. For example, galanthamine and huperzine A are alkaloid derivatives currently being used for the symptomatic management of neurodegenerative disease. The etiology of neurodegenerative diseases is polygenic and multifactorial including but not limited to inflammation, oxidative stress and protein aggregation. Therefore, natural-product-based alkaloids with polypharmacology modulation properties are potentially useful for further drug development or, to a lesser extent, as nutraceuticals to manage neurodegeneration. This review aims to discuss and summarise recent developments in relation to naturally derived alkaloids for neurodegenerative diseases.

Matched MeSH terms: Neuroprotective Agents/chemistry
Synthesized 2-Trifluoromethylquinazolines and Quinazolinones Protect BV2 and N2a Cells against LPS- and H2O2-induced Cytotoxicity

Nallathamby N, Phan CW, Sova M, Saso L, Sabaratnam V

Med Chem, 2021;17(6):623-629.
PMID: 31849289 DOI: 10.2174/1573406416666191218095635

BACKGROUND: Microglia are associated with neuroinflammation, which play a key role in the pathogenesis of neurodegenerative diseases. It has been reported that some quinazolines and quinazolinones possess anti-inflammatory properties. However, the pharmacological properties of certain quinazoline derivatives are still unknown.
OBJECTIVE: The antioxidant, cytotoxic, and protective effects of a series of synthesized 2- trifluoromethylquinazolines (2, 4, and 5) and quinazolinones (6-8) in lipopolysaccharide (LPS)- murine microglia (BV2) and hydrogen peroxide (H2O2)-mouse neuroblastoma-2a (N2a) cells were investigated.
METHOD: The antioxidant activity of synthesized compounds was evaluated with ABTS and DPPH assays. The cytotoxic activities were determined by MTS assay in BV2 and N2a cells. The production of nitric oxide (NO) in LPS-induced BV2 microglia cells was quantified.
RESULTS: The highest ABTS and DPPH scavenging activities were observed for compound 8 with 87.7% of ABTS scavenge percentage and 54.2% DPPH inhibition. All compounds were noncytotoxic in BV2 and N2a cells at 5 and 50 μg/mL. The compounds which showed the highest protective effects in LPS-induced BV2 and H2O2-induced N2a cells were 5 and 7. All tested compounds, except 4, also reduced NO production at concentrations of 50 μg/mL. The quinazolinone series 6-8 exhibited the highest percentage of NO reduction, ranging from 38 to 60%. Compounds 5 and 8 possess balanced antioxidant and protective properties against LPS- and H2O2-induced cell death, thus showing great potential to be developed into anti-inflammatory and neuroprotective agents.
CONCLUSION: Compounds 5 and 7 were able to protect the BV2 and N2a cells against LPS and H2O2 toxicity, respectively, at a low concentration (5 μg/mL). Compounds 6-8 showed potent reduction of NO production in BV2 cells.

Matched MeSH terms: Neuroprotective Agents/chemistry
Deep eutectic solvent mediated synthesis of 3,4-dihydropyrimidin-2(1H)-ones and evaluation of biological activities targeting neurodegenerative disorders

Saleem Khan M, Asif Nawaz M, Jalil S, Rashid F, Hameed A, Asari A, et al.

Bioorg Chem, 2022 01;118:105457.
PMID: 34798458 DOI: 10.1016/j.bioorg.2021.105457

Substitution of hazardous and often harmful organic solvents with "green" and "sustainable" alternative reaction media is always desirous. Ionic liquids (IL) have emerged as valuable and versatile liquids that can replace most organic solvents in a variety of syntheses. However, recently new types of low melting mixtures termed as Deep Eutectic Solvents (DES) have been utilized in organic syntheses. DES are non-volatile in nature, have sufficient thermal stability, and also have the ability to be recycled and reused. Hence DES have been used as alternative reaction media to perform different organic reactions. The availability of green, inexpensive and easy to handle alternative solvents for organic synthesis is still scarce, hence our interest in DES mediated syntheses. Herein we have investigated Biginelli reaction in different DES for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones. Monoamine oxidases and cholinesterases are important drug targets for the treatment of various neurological disorders such as Alzheimer's disease, Parkinson's disease, depression and anxiety. The compounds synthesized herein were evaluated for their inhibitory potential against these enzymes. Some of the compounds were found to be highly potent and selective inhibitors. Compounds 1 h and 1c were the most active monoamine oxidase A (MAO A) (IC50 = 0.31 ± 0.11 µM) and monoamine oxidase B (MAO B) (IC50 = 0.34 ± 0.04 µM) inhibitors respectively. All compounds were selective AChE inhibitors and did not inhibit BChE (<29% inhibition). Compound 1 k (IC50 = 0.13 ± 0.09 µM) was the most active AChE inhibitor.

Matched MeSH terms: Neuroprotective Agents/chemistry
In silico studies, synthesis and pharmacological evaluation to explore multi-targeted approach for imidazole analogues as potential cholinesterase inhibitors with neuroprotective role for Alzheimer's disease

Gurjar AS, Darekar MN, Yeong KY, Ooi L

Bioorg Med Chem, 2018 05 01;26(8):1511-1522.
PMID: 29429576 DOI: 10.1016/j.bmc.2018.01.029

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with multiple factors associated with its pathogenesis. Our strategy against AD involves design of multi-targeted 2-substituted-4,5-diphenyl-1H-imidazole analogues which can interact and inhibit AChE, thereby, increasing the synaptic availability of ACh, inhibit BuChE, relieve induced oxidative stress and confer a neuroprotective role. Molecular docking was employed to study interactions within the AChE active site. In silico ADME study was performed to estimate pharmacokinetic parameters. Based on computational studies, some analogues were synthesized and subjected to pharmacological evaluation involving antioxidant activity, toxicity and memory model studies in animals followed by detailed mechanistic in vitro cholinesterase inhibition study. Amongst the series, analogue 13 and 20 are the most promising multi-targeted candidates which can potentially increase memory, decrease free radical levels and protect neurons against cognitive deficit.

Matched MeSH terms: Neuroprotective Agents/chemistry
Preconditioning effect of (S)-3,5-dihydroxyphenylglycine on ischemic injury in middle cerebral artery occluded Sprague-Dawley rats

Nik Ramli NN, Omar N, Husin A, Ismail Z, Siran R

Neurosci Lett, 2015 Feb 19;588:137-41.
PMID: 25562631 DOI: 10.1016/j.neulet.2014.12.062

Glutamate receptors are the integral cellular components associated with excitotoxicity mechanism induced by the ischemic cascade events. Therefore the glutamate receptors have become the major molecular targets of neuroprotective agents in stroke researches. Recent studies have demonstrated that a Group I metabotropic glutamate receptor agonist, (S)-3,5-dihydroxyphenylglycine ((S)-3,5-DHPG) preconditioning elicits neuroprotection in the hippocampal slice cultures exposed to toxic level of N-methyl-d-aspartate (NMDA). We further investigated the preconditioning effects of (S)-3,5-DHPG on acute ischemic stroke rats. One 10 or 100μM of (S)-3,5-DHPG was administered intrathecally to Sprague-Dawley adult male rats, 2h prior to induction of acute ischemic stroke by middle cerebral artery occlusion (MCAO). After 24h, neurological deficits were evaluated by modified stroke severity scores and grid-walking test. All rats were sacrificed and infarct volumes were determined by 2,3,5-triphenyltetrazolium chloride staining. The serum level of neuron-specific enolase (NSE) of each rat was analyzed by enzyme-linked immunosorbent assay (ELISA). One and 10μM of (S)-3,5-DHPG preconditioning in the stroke rats showed significant improvements in motor impairment (P<0.01), reduction in the infarct volume (P<0.01) and reduction in the NSE serum level (P<0.01) compared to the control stroke rats. We conclude that 1 and 10μM (S)-3,5-DHPG preconditioning induced protective effects against acute ischemic insult in vivo.

Matched MeSH terms: Neuroprotective Agents/chemistry
Merging memantine and ferulic acid to probe connections between NMDA receptors, oxidative stress and amyloid-β peptide in Alzheimer's disease

Rosini M, Simoni E, Caporaso R, Basagni F, Catanzaro M, Abu IF, et al.

Eur J Med Chem, 2019 Oct 15;180:111-120.
PMID: 31301562 DOI: 10.1016/j.ejmech.2019.07.011

N-methyl-d-aspartate receptors (NMDAR) are critically involved in the pathogenesis of Alzheimer's disease (AD). Acting as an open-channel blocker, the anti-AD drug memantine preferentially targets NMDAR overactivation, which has been proposed to trigger neurotoxic events mediated by amyloid β peptide (Aβ) and oxidative stress. In this study, we applied a multifunctional approach by conjugating memantine to ferulic acid, which is known to protect the brain from Aβ neurotoxicity and neuronal death caused by ROS. The most interesting compound (7) behaved, like memantine, as a voltage-dependent antagonist of NMDAR (IC50 = 6.9 μM). In addition, at 10 μM concentration, 7 exerted antioxidant properties both directly and indirectly through the activation of the Nrf-2 pathway in SH-SY5Y cells. At the same concentration, differently from the parent compounds memantine and ferulic acid alone, it was able to modulate Aβ production, as revealed by the observed increase of the non-amyloidogenic sAPPα in H4-SW cells. These findings suggest that compound 7 may represent a promising tool for investigating NMDAR-mediated neurotoxic events involving Aβ burden and oxidative damage.

Matched MeSH terms: Neuroprotective Agents/chemistry
2-Furoic piperazide derivatives as promising drug candidates of type 2 diabetes and Alzheimer's diseases: In vitro and in silico studies

Abbasi MA, Hassan M, Ur-Rehman A, Siddiqui SZ, Hussain G, Shah SAA, et al.

Comput Biol Chem, 2018 Dec;77:72-86.
PMID: 30245349 DOI: 10.1016/j.compbiolchem.2018.09.007

The heterocyclic compounds have been extensively reported for their bioactivity potential. The current research work reports the synthesis of some new multi-functional derivatives of 2-furoic piperazide (1; 1-(2-furoyl)piperazine). The synthesis was initiated by reacting the starting compound 1 with 3,5-dichloro-2-hydroxybenzenesulfonyl chloride (2) in a basic, polar and protic medium to obtain the parent sulfonamide 3 which was then treated with different electrophiles, 4a-g, in a polar and aprotic medium to acquire the designed molecules, 5a-g. These convergent derivatives were evaluated for their inhibitory potential against α-glucosidase, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. Acarbose was used as a reference standard for α-glucosidase inhibition while eserine for AChE and BChE inhibition. Some of the synthesized compounds were identified as promising inhibitors of these three enzymes and their bioactivity potentials were also supported by molecular docking study. The most active compounds among the synthetic analogues might be helpful in drug discovery and development for the treatment of type 2 diabetes and Alzhiemer's diseases.

Matched MeSH terms: Neuroprotective Agents/chemistry

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