scholarly journals Synthesis and AChE Inhibitory Activity of Novel Thiazolylhydrazone Derivatives

Molecules ◽  
2019 ◽  
Vol 24 (13) ◽  
pp. 2392 ◽  
Author(s):  
Derya Osmaniye ◽  
Begüm Nurpelin Sağlık ◽  
Ulviye Acar Çevik ◽  
Serkan Levent ◽  
Betül Kaya Çavuşoğlu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Inhibitory Activity ◽  
New Drugs ◽  
Brain Diseases ◽  
Structure Identification ◽  
Ache Inhibitor ◽  
In Vitro Tests ◽  
Active Inhibitor

Alzheimer’s disease (AD) is the most common of the degenerative brain diseases and is described together with the impairment of cognitive function. Patients with AD lose the capability to code new memories, and life conditions are extremely difficult. The development of new drugs in this area continues at a great pace. A novel series of thiazole-piperazine hybrids, aimed against Alzheimer’s disease (AD), have been synthesized. The structure identification of synthesized compounds was elucidated by 1HNMR, 13C-NMR, and LCMSMS spectroscopic methods. The inhibitory potential of the synthesized compounds on cholinesterase enzymes was investigated. The compounds 3a, 3c and 3i showed significant inhibitory activity on the acetylcholinesterase (AChE) enzyme. On the other hand, none of the compounds showed significant inhibitory activity on the butyrylcholinesterase (BChE) enzyme. In addition to enzyme inhibition studies, enzyme kinetic studies were performed to observe the effects of the most active inhibitor compounds on the substrate–enzyme relationship. In addition to in vitro tests, docking studies also indicated that compound 3c potentially acts as a dual binding site AChE inhibitor.

Natural Anti-inflammatory compounds as Drug candidates in Alzheimer’s disease

2020 ◽  
Vol 27 ◽  
Author(s):  
Reyaz Hassan Mir ◽  
Abdul Jalil Shah ◽  
Roohi Mohi-ud-din ◽  
Faheem Hyder Potoo ◽  
Mohd. Akbar Dar ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Natural Products ◽  
Protective Action ◽  
New Drugs ◽  
Huperzine A ◽  
Brain Disorder ◽  
Anti Inflammatory

: Alzheimer's disease (AD) is a chronic neurodegenerative brain disorder characterized by memory impairment, dementia, oxidative stress in elderly people. Currently, only a few drugs are available in the market with various adverse effects. So to develop new drugs with protective action against the disease, research is turning to the identification of plant products as a remedy. Natural compounds with anti-inflammatory activity could be good candidates for developing effective therapeutic strategies. Phytochemicals including Curcumin, Resveratrol, Quercetin, Huperzine-A, Rosmarinic acid, genistein, obovatol, and Oxyresvertarol were reported molecules for the treatment of AD. Several alkaloids such as galantamine, oridonin, glaucocalyxin B, tetrandrine, berberine, anatabine have been shown anti-inflammatory effects in AD models in vitro as well as in-vivo. In conclusion, natural products from plants represent interesting candidates for the treatment of AD. This review highlights the potential of specific compounds from natural products along with their synthetic derivatives to counteract AD in the CNS.

Spirocyclohexadienones as an Uncommon Scaffold for Acetylcholinesterase Inhibitory Activity

2019 ◽  
Vol 15 (4) ◽  
pp. 373-382 ◽  
Author(s):  
Ralph C. Gomes ◽  
Renata P. Sakata ◽  
Wanda P. Almeida ◽  
Fernando Coelho
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Population Aging ◽  
Acetylcholinesterase Inhibitors ◽  
Acetylcholinesterase Activity ◽  
Docking Study ◽  
Biological Properties ◽  
Ache Inhibitor ◽  
Molecular Docking Study

Background: The most important cause of dementia affecting elderly people is the Alzheimer’s disease (AD). Patients affected by this progressive and neurodegenerative disease have severe memory and cognitive function impairments. Some medicines used for treating this disease in the early stages are based on inhibition of acetylcholinesterase. Population aging should contribute to increase the cases of patients suffering from Alzheimer's disease, thus requiring the development of new therapeutic entities for the treatment of this disease. Methods: The objective of this work is to identify new substances that have spatial structural similarity with donepezil, an efficient commercial drug used for the treatment of Alzheimer's disease, and to evaluate the capacity of inhibition of these new substances against the enzyme acetylcholinesterase. Results: Based on a previous results of our group, we prepared a set of 11 spirocyclohexadienones with different substitutions patterns in three steps and overall yield of up to 59%. These compounds were evaluated in vitro against acetylcholinesterase. We found that eight of them are able to inhibit the acetylcholinesterase activity, with IC50 values ranging from 0.12 to 12.67 µM. Molecular docking study indicated that the spirocyclohexadienone, 9e (IC50 = 0.12 µM), a mixedtype AChE inhibitor, showed a good interaction at active site of the enzyme, including the cationic (CAS) and the peripheral site (PAS). Conclusion: We described the first study aimed at investigating the biological properties of spirocyclohexadienones as acetylcholinesterase inhibitors. Thus, we have identified an inhibitor, which provided valuable insights for further studies aimed at the discovery of more potent acetylcholinesterase inhibitors.

SEMI-SYNTHESIS AND EVALUATION OF HESPERETIN DERIVATIVES AS ACETYLCHOLINESTERASE INHIBITORS7

2018 ◽  
Vol 8 (4) ◽  
pp. 7-12
Author(s):  
Huan Tran The ◽  
Dao Tran Thanh
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Key Words ◽  
Inhibitory Activity ◽  
Acetylcholinesterase Inhibitory Activity ◽  
Ic50 Value ◽  
Ellman’S Method ◽  
Further Development ◽  
Derivatives Of

Background: Inhibition of acetylcholinesterase are regarded as one of promising approach to treat Alzheimer’s disease. Hesperetin is a potential flavonoid for further development in this direction. Objectives: Semi-synthesized and assayed for hesperetin derivatives’s acetylcholinesterase inhibitory activity in vitro. Materials and methods: Ester and ether derivatives of hesperetin were semi-synthesized. The semi-synthesis compounds were tested for acetylcholinesterase inhibitory activity in vitro according to the Ellman’s method. Results: Hesperetin is obtained by hydrolysing hesperidin. Then, two ester and two ether derivatives were semi-synthesized from hesperetin. The results showed that some of the semi-synthesis hesperetin derivatives displayed stronger acetylcholinesterase inhibitory activity than hesperetin. Among them, derivative 1 has the best activity with an IC50 value of 43.50 μM. Conclusions: Four hesperetin derivatives were semi-synthesized and investigated their acetylcholinesterase inhibitory activity, some of which showed improvement in activity. Key words: Hesperetin, semi-synthesis, inhibit, enzyme, acetylcholinesterase

Design and Synthesis of Novel Aminoalkanamides Targeting Neurodegeneration and Symptoms of Alzheimer’s Disease

2021 ◽  
Vol 28 ◽  
Author(s):  
Agnieszka Jankowska ◽  
Grzegorz Satała ◽  
Gniewomir Latacz ◽  
Anna Partyka ◽  
Annamaria Lubelska ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Inhibitory Activity ◽  
Neuroprotective Effect ◽  
Antidepressant Activity ◽  
Receptor Affinity ◽  
Design And Synthesis ◽  
Novel Drugs ◽  
Adme Properties

Background: There is currently no drug that slows the process of neurodegeneration or alleviates the cognitive and depressive symptoms in patients with Alzheimer’s disease. Due to the increasing number of Alzheimer’s patients, there is an urgent need to develop novel drugs with neuroprotective, procognitive, and antidepressant properties. Objective: The aim of this study was to design, synthesize, and evaluate novel aminoalkanamides with serotonin 5-HT1A/5-HT7 receptor affinity and phosphodiesterase (PDE) inhibitory activity as a new approach to combat neurodegeneration and symptoms of Alzheimer’s disease. Methods: The newly designed compounds were synthesized using classical methods of organic chemistry and tested in vitro for their receptor affinity, functional profile, enzyme inhibition, and ADME properties. The neuroprotective effect against H2O2-induced increase of reactive oxygen species level was tested in SH-SY5Y cells. The novel object recognition and forced swimming tests were used to evaluate the procognitive and antidepressant activity, respectively. Results: Synthesized aminoalkanamides were characterized as potent 5-HT1A receptor antagonists with additional 5-HT7 receptor antagonistic properties and PDE4B inhibitory activity. Selected compound 15 showed neuroprotective, procognitive, and antidepressant properties. In addition, compound 15 revealed suitable ADME properties expressed as a good membrane permeability and a high metabolic stability. Conclusion: This study revealed a new class of compounds that may be useful in the search for an effective drug in the alleviation of neurodegeneration and symptoms of Alzheimer’s disease.

Multifunctional Ligands with Glycogen Synthase Kinase 3 Inhibitory Activity as a New Direction in Drug Research for Alzheimer’s Disease

2020 ◽  
Vol 27 ◽  
Author(s):  
Agnieszka Jankowska ◽  
Grzegorz Satała ◽  
Andrzej J. Bojarski ◽  
Maciej Pawłowski ◽  
Grażyna Chłoń-Rzepa
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Models ◽  
Inhibitory Activity ◽  
Glycogen Synthase ◽  
Neuropsychiatric Symptoms ◽  
New Drugs ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Multifunctional Ligands

: Alzheimer’s disease (AD) belongs to the most common forms of dementia that causes a progressive loss of brain cells and leads to memory impairment and decline of other thinking skills. There is yet no effective treatment for AD; hence, the search for new drugs that could improve memory and other cognitive functions is one of the hot research topics worldwide. Scientific efforts are also directed toward combating behavioral and psychological symptoms of dementia, which are an integral part of the disease. Several studies have indicated that glycogen synthase kinase 3 beta (GSK3β) plays a crucial role in the pathogenesis of AD. Moreover, GSK3β inhibition provided beneficial effects on memory improvement in multiple animal models of AD. The present review aimed to update the most recent reports on the discovery of novel multifunctional ligands with GSK3β inhibitory activity as potential drugs for the symptomatic and disease-modifying therapy of AD. Compounds with GSK3β inhibitory activity seem to be an effective pharmacological approach for treating the causes and symptoms of AD as they reduced neuroinflammation and pathological hallmarks in animal models of AD and provided relief from cognitive and neuropsychiatric symptoms. These compounds have the potential to be used as drugs for the treatment of AD, but their precise pharmacological, pharmacokinetic, toxicological, and clinical profiles need to be defined.

Development of Phthalimide-Donepezil Hybrids as Potent Multitarget- Directed Ligands for the Treatment of Alzheimer’s Disease

2020 ◽  
Vol 17 (9) ◽  
pp. 1155-1163
Author(s):  
Lintao Yu ◽  
Jian Shi ◽  
Xinfeng Cheng ◽  
Keren Wang ◽  
Shuang Liu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Inhibitory Activity ◽  
Biological Activities ◽  
Docking Study ◽  
Binding Mode ◽  
Mao B ◽  
Ic50 Value ◽  
Ache Inhibitory Activity

Background: Due to the complex etiology of AD, multi-target-directed ligands (MTDLs), combining two or more distinct pharmacological moieties, have been developed in both symptomatic and disease-modifying efficiencies and are considered as an effective way for the treatment of AD. Methods: To test their biological activities, including AChE/BChE inhibitory activity and MAOA/ MAO-B inhibitory activity. In addition, molecular modeling studies were performed to afford insight into the binding mode. Results: The results displayed that compound 4c showed the best AChE inhibitory activity with an IC50 value of 4.2 μM, which was supported by the kinetic study and docking study. Compound 4c was also a selective MAO-B inhibitor (IC50 = 8.2 μM). Moreover, compound 4c could cross the blood-brain barrier in vitro. Conclusion: Compound 4c deserved to further study as a potential multifunctional agent for the treatment of Alzheimer’s disease.

scholarly journals Study of 3-(4’-Nitrobenzamido)coumarin using an Alzheimer’s Disease Model

2021 ◽  
Author(s):  
Fernanda Rodríguez-Enríquez ◽  
Dolores Viña ◽  
Eugenio Uriarte ◽  
José Ángel Fontenla ◽  
Maria João Matos
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Object Recognition ◽  
Disease Model ◽  
Pharmacokinetic Profile ◽  
Ache Inhibitor ◽  
Mice Model ◽  
Object Recognition Test

Abstract 3-(4’-Nitrobenzamido)coumarin (MJM255), a potent in vitro acetylcholinesterase (AChE) inhibitor, was selected as an in vivo candidate for the discovery of new therapeutic solutions for Alzheimer’s disease. Computational (in silico) studies showing the theoretical physicochemical properties indicate desirable a pharmacokinetic profile for this molecule to cross the blood-brain barrier (BBB). An in vivo study, using the object recognition test (ORT) mice model, was carried out. This compound exhibited a similar effect as eserine, a well-known AChE inhibitor able to cross the BBB.

scholarly journals Essential Oil of Lippia origanoides H.B.K.: A Promising Compound Acetylcholinesterase Inhibitors for the Treatment of Alzheimer’s Disease

2021 ◽  
Author(s):  
Aldenora Maria Ximenes Rodrigues ◽  
Brenda Nayranne Gomes dos Santos ◽  
Ranyelison Silva Machado ◽  
Rubens Renato de Sousa Carmo ◽  
Matheus Pedrosa de Oliveira ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Essential Oil ◽  
In Silico ◽  
Acetylcholinesterase Inhibitors ◽  
Acetylcholinesterase Activity ◽  
New Drugs ◽  
Gas Chromatography Mass Spectrometry ◽  
Low Toxicity

Alzheimer's disease is characterized by a progressive decline of cognitive functions. The class of drugs used for the treatment are acetylcholinesterase inhibitors. Essential oils have contributed to folk medicine and discovery of new drugs for a long time. The purpose of the study was to investigate the in vitro and in silico the anti-acetylcholinesterase activity, as well as acute toxicity of the essential oil of Lippia origanoides. EOLO was obtained by hydrostelting and analyzed by gas chromatography-mass spectrometry. The inhibition assay of acetylcholinesterase enzyme activity was evaluated in vitro, as well as in silico by docking. The effects of EOLO on hematological, biochemical and behavioral parameters were analyzed in mices. We expose that EOLO shows good anti-acetylcholinesterase activity and low toxicity, possibly resulting from the action of the majority compounds thymol, carvacrol and p-cymene. The anti-acetylcholinesterase potential in vitro demonstrating a 70% inhibition. The docking results elucidated the participation of the major phenolics in AChE inhibition by interacting with the catalytic cavity of AchE. The acute oral toxicity test classified as low toxicity. These results contribute to expand the knowledge about essential oil of Lippia origanoides. Therefore, appears to be promising for herbal medicine production with anti-acetylcholinesterase and antioxidant activity.

scholarly journals The Ameliorating Effect of Phenylsulfonamide Derivatives on Scopolamine-Induced Memory Impairment in Mice via Inhibition of mPGES-1

Proceedings ◽  
2019 ◽  
Vol 22 (1) ◽  
pp. 36
Author(s):  
Ryu ◽  
Moon ◽  
Ko ◽  
Lee ◽  
Lee
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Inhibitory Activity ◽  
Memory Impairment ◽  
Close Correlation ◽  
Positive Control ◽  
Raw 264.7 Macrophage Cells ◽  
Continuous Work ◽  
Cox 1

Our previous research showed that a novel series of phenylsulfonyl hydrazide derivatives reduced LPS-induced PGE2 levels in RAW 264.7 macrophage cells via an inhibition of mPGES-1 enzyme. As a continuous work, new phenylsulfonamide derivatives (5a-5k) as methylene analogues of phenylsulfonyl hydrazide derivatives, including MPO-0063, were synthesized and biologically evaluated in vitro. Among synthetic compounds, 5a (MPO-0112) showed decreased inhibitory activity against PGE2 production (IC50: 0.34 µM) compared to MPO-0063 (IC50: 0.04 µM) but inhibited the mPGES-1 enzyme (IC50: 7.37 µM) similar to MPO-0063 (IC50: 0.10 µM) together with excellent selectivity over COX-enzymes (COX-1 and 2). According to recent studies on the close correlation between up-regulation of mPGES-1 and Alzheimer's disease, we investigated whether 5a could ameliorate scopolamine-induced memory impairment using the passive avoidance test. The memory impairment-ameliorating effect of 5a (1.0 mg/kg, p.o.) was found to be effective, comparable to that of donepezil (5 mg/kg, p.o.) as a positive control. On the other hand, 5a exhibited little or weak AChE and BuChE inhibitory activity, which implies that 5a could ameliorate scopolamine-induced memory impairment by inhibiting mPGES-1 enzyme instead of cholinesterase enzymes. In addition, MPO-0112 exhibited a favorable in vitro CYP profile, which is suggestive of no potential drug–drug interactions. Therefore, these overall results suggest that 5a as a selective mPGES-1 inhibitor may be a novel therapeutic agent for diseases associated with cognitive deficits, such as Alzheimer’s disease.

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