Ethyl Acetohydroxamate Incorporated Chalcones: Unveiling a Novel Class of Chalcones for Multitarget Monoamine Oxidase-B Inhibitors Against Alzheimer’s Disease

2019 ◽  
Vol 18 (8) ◽  
pp. 643-654 ◽  
Author(s):  
Reeta ◽  
Seung Cheol Baek ◽  
Jae Pil Lee ◽  
T.M. Rangarajan ◽  
Ayushee ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Monoamine Oxidase ◽  
Target Prediction ◽  
Inhibitory Effect ◽  
Monoamine Oxidase A ◽  
Mao B ◽  
Drug Molecules ◽  
Ic50 Value ◽  
Ic50 Values

Background: Chalcones are considered as the selective scaffold for the inhibition of MAO-B. Objective: A previously synthesized ethyl acetohydroxamate-chalcones (L1-L22) were studied for their inhibitory activities against human recombinant monoamine oxidase A and B (hMAO-A and hMAO-B, respectively) and acetylcholinesterase (AChE) as multi-target directed ligands for the treatment of Alzheimer’s Disease (AD). Methods: Enzyme inhibition studies of MAO-A, MAO-B and AChE is carried out. Computational studies such as Molecular docking, Molecular Mechanics/Generalized Born Surface Area calculations, ADMET prediction, and protein target prediction are also performed. Results: Among the screened compounds, compound L3 has most potent hMAO-B inhibition with an IC50 value of 0.028 ± 0.0016 µM, and other compounds, L1, L2, L4, L8, L12, and L21 showed significant potent hMAO-B inhibition with IC50 values of 0.051 ± 0.0014, 0.086 ± 0.0035, 0.036 ± 0.0011, 0.096 ± 0.0061, 0.083 ± 0.0016, and 0.038 ± 0.0021 µM, respectively. On the other hand, among the tested compounds, compound L13 showed highest hMAO-A inhibition with an IC50 value of 0.51± 0.051 µM and L9 has a significant value of 1.85 ± 0.045 µM. However, the compounds L3 and L4 only showed high selectivities for hMAO-B with Selectivity Index (SI) values of 621.4 and 416.7, respectively. Among the substituents in ring A of ethyl acetohydroxamate-chalcones (L1-L9), F atom at p-position (L3) showed highest inhibitory effect against hMAO-B. This result supports the uniqness and bizarre behavior of fluorine. Moreover, chalcones L3, L4, L9, L11, and L12 showed potential AChE inhibitory effect with IC50 values of 0.67, 0.85, 0.39, 0.30, and 0.45 µM, respectively. Inhibitions of hMAO-B by L3 or L4 were recovered to the level of the reversible reference (lazabemide), and were competitive with Ki values of 0.0030 ± 0.0002 and 0.0046 ± 0.0005 µM, respectively. Inhibitions of AChE by L3 and L11 were of the competitive and mixed types with Ki values of 0.30 ± 0.044 and 0.14 ± 0.0054 µM, respectively. Conclusion: The studies indicated that L3 and L4 are considered to be promising multitarget drug molecules with potent, selective, and reversible competitive inhibitors of hMAO-B and with highly potent AChE inhibitory effect.

scholarly journals Role of Monoamine Oxidase Activity in Alzheimer’s Disease: An Insight into the Therapeutic Potential of Inhibitors

Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3724
Author(s):  
Tapan Behl ◽  
Dapinder Kaur ◽  
Aayush Sehgal ◽  
Sukhbir Singh ◽  
Neelam Sharma ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Monoamine Oxidase ◽  
Therapeutic Potential ◽  
Neuronal Loss ◽  
Monoamine Oxidase A ◽  
Mao B ◽  
Psychiatric Conditions ◽  
Preclinical And Clinical Studies

Despite not being utilized as considerably as other antidepressants in the therapy of depression, the monoamine oxidase inhibitors (MAOIs) proceed to hold a place in neurodegeneration and to have a somewhat broad spectrum in respect of the treatment of neurological and psychiatric conditions. Preclinical and clinical studies on MAOIs have been developing in recent times, especially on account of rousing discoveries manifesting that these drugs possess neuroprotective activities. The altered brain levels of monoamine neurotransmitters due to monoamine oxidase (MAO) are directly associated with various neuropsychiatric conditions like Alzheimer’s disease (AD). Activated MAO induces the amyloid-beta (Aβ) deposition via abnormal cleavage of the amyloid precursor protein (APP). Additionally, activated MAO contributes to the generation of neurofibrillary tangles and cognitive impairment due to neuronal loss. No matter the attention of researchers on the participation of MAOIs in neuroprotection has been on monoamine oxidase-B (MAO-B) inhibitors, there is a developing frame of proof indicating that monoamine oxidase-A (MAO-A) inhibitors may also play a role in neuroprotection. The therapeutic potential of MAOIs alongside the complete understanding of the enzyme’s physiology may lead to the future advancement of these drugs.

scholarly journals Development of Halogenated Pyrazolines as Selective Monoamine Oxidase-B Inhibitors: Deciphering via Molecular Dynamics Approach

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3264
Author(s):  
Aathira Sujathan Nair ◽  
Jong-Min Oh ◽  
Vishal Payyalot Koyiparambath ◽  
Sunil Kumar ◽  
Sachithra Thazhathuveedu Sudevan ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Monoamine Oxidase ◽  
Phenyl Ring ◽  
Competitive Inhibitor ◽  
Selectivity Index ◽  
Monoamine Oxidase A ◽  
Mao B ◽  
Ic50 Value ◽  
The Central Nervous System ◽  
Inhibitory Activities

Halogens have been reported to play a major role in the inhibition of monoamine oxidase (MAO), relating to diverse cognitive functions of the central nervous system. Pyrazoline/halogenated pyrazolines were investigated for their inhibitory activities against human monoamine oxidase-A and -B. Halogen substitutions on the phenyl ring located at the fifth position of pyrazoline showed potent MAO-B inhibition. Compound 3-(4-ethoxyphenyl)-5-(4-fluorophenyl)-4,5-dihydro-1H-pyrazole (EH7) showed the highest potency against MAO-B with an IC50 value of 0.063 µM. The potencies against MAO-B were increased in the order of –F (in EH7) > –Cl (EH6) > –Br (EH8) > –H (EH1). The residual activities of most compounds for MAO-A were > 50% at 10 µM, except for EH7 and EH8 (IC50 = 8.38 and 4.31 µM, respectively). EH7 showed the highest selectivity index (SI) value of 133.0 for MAO-B, followed by EH6 at > 55.8. EH7 was a reversible and competitive inhibitor of MAO-B in kinetic and reversibility experiments with a Ki value of 0.034 ± 0.0067 µM. The molecular dynamics study documented that EH7 had a good binding affinity and motional movement within the active site with high stability. It was observed by MM-PBSA that the chirality had little effect on the overall binding of EH7 to MAO-B. Thus, EH7 can be employed for the development of lead molecules for the treatment of various neurodegenerative disorders.

Effect of amiridine and tacrine, drugs effective in Alzheimer's disease, on monoamine oxidase A and B activity

1992 ◽  
Vol 113 (2) ◽  
pp. 190-192
Author(s):  
Yu. V. Burov ◽  
T. D. Baimanov ◽  
L. V. Tat'yanenko ◽  
N. M. Sokolova ◽  
I. M. Tereshchenkova
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Monoamine Oxidase ◽  
Monoamine Oxidase A

Monoamine Oxidase A Polymorphism in Brazilian Patients: Risk Factor for Late-Onset Alzheimer's Disease?

2005 ◽  
Vol 27 (2) ◽  
pp. 213-218 ◽  
Author(s):  
Agnes L. Nishimura ◽  
Camila Guindalini ◽  
João R. M. Oliveira ◽  
Ricardo Nitrini ◽  
Valéria S. Bahia ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Factor ◽  
Monoamine Oxidase ◽  
Late Onset ◽  
Monoamine Oxidase A

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 Relationship between the monoamine oxidase gene overactivity and the other pathophysiological and behavioral parameters implicated in memory deficiency in albino Winstar rats as Alzheimer’s disease model

2021 ◽  
Vol 13 (4) ◽  
pp. 1274-1282
Author(s):  
Halla Abdul-Hadi Chabuk ◽  
Zahraa Isam Jameel
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Antioxidant Activity ◽  
Monoamine Oxidase ◽  
Disease Model ◽  
Amyloid Β ◽  
Treated Group ◽  
Monoamine Oxidase A ◽  
Exon 2 ◽  
Mao A

The current study aimed to assess the pathophysiology mechanisms that mediate the effect on albin winstar rats' memory induced by the co -administration of fluoride and aluminum sulfate, as a model of Alzheimer's disease. This was done by assessing monoamine oxidase-A (MAO-A) activity, antioxidant activity, H2O2  and amyloid-β concentration in the hippocampus, embedded deep into the brain's temporal lobe, and level of cytokines in serum. The polymerase chain reaction approach was used to genotyping MAO-A, followed by single -stranded conformational polymorphism (SSCP) coupled with sequencing technique. The experimental animals were divided into two groups: control and treated groups. The uptake of heavy metals led to significantly increased MAO-A activity, amyloid -β deposition, H2O2 and cytokines levels in the treated group. However, the finding showed a significant decrease in antioxidant activity in the treated group. The results indicated that metals caused memory and learning impairments. PCR -SSCP genotyping showed many SNPs and haplotypes of the MAO-A exon 2 region, which showed the MAO-A gene polymorphism changes associated with Alzheimer's disease. The overall results indicated a role of metals to induce oxidative stress stimulating pathophysiological hallmarks in the hippocampus due to an increase in the influx of monoamine oxidase expression, which has been implicated in impaired memory, this study focused on the genetic variation of the exon 2 in monoamine oxidase-A gene and its relationship to Alzheimer's disease with the presence of several single nucleotide polymorphisms that may be related to Alzheimer's disease model in rats.

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