Synthesis and in vitro Assay of New Triazole Linked Decursinol Derivatives Showing Inhibitory Activity against Cholinesterase for Alzheimer’s Disease Therapeutics

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.

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SEMI-SYNTHESIS AND EVALUATION OF HESPERETIN DERIVATIVES AS ACETYLCHOLINESTERASE INHIBITORS7

Journal of Medicine and Pharmacy ◽

10.34071/jmp.2018.4.1 ◽

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

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

Current Medicinal Chemistry ◽

10.2174/0929867328666210215113346 ◽

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.

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PTP1B INHIBITORS FROM ISODON TERNIFOLIUS COLLECTED IN VIETNAM

Vietnam Journal of Science and Technology ◽

10.15625/2525-2518/58/5/15012 ◽

2020 ◽

Vol 58 (5) ◽

pp. 533

Author(s):

Nguyen Phi-Hung

Keyword(s):

Enzyme Activity ◽

Inhibitory Activity ◽

In Vitro Assay ◽

Vitro Assay ◽

Chemical Structures ◽

Whole Plant ◽

Ic50 Values ◽

Ptp1b Inhibitors ◽

First Time

From the whole plant of Isodon ternifolius collected in Vietnam, four triterpens including ursaldehyde (1), ursolic acid (2), b-sitosterol (3) and b-sitosteryl ferulate (4) were purified. Their chemical structures were determined by interpretation of NMR and MS data and comparison with the literatures. Compounds 1-4 were evaluated for their inhibitory activity against PTP1B enzyme activity using in vitro assay. Compounds 1 and 2 displayed potential activities with IC50 values of 16.92 ± 0.12 and 3.42 ± 0.45 μM, respectively. This is the first time that compounds 1 and 4 have been isolated from the Isodon genus and I. ternifolius has been evaluated for the PTP1B inhibitory activity.

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

Letters in Drug Design & Discovery ◽

10.2174/1570180817999200420120519 ◽

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.

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