Dual Inhibitors of Cholinesterases and Monoamine Oxidases for Alzheimer’S Disease

Knez, Damijan; Sova, Matej; Košak, Urban; Gobec, Stanislav

doi:10.4155/fmc-2017-0036

Cited by 46 publications

(31 citation statements)

References 119 publications

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“…Growing from this evidence, the development of multi‐target compounds with simultaneous inhibition of ChEs and MAO−B may provide more benefits for the AD treatment . Dual inhibition of MAO−B and ChE not only improves the level of ACh and but also reduces the oxidative stress by decreases the plaques deposition in the AD brain . Earlier studies document that inhibition of MAO−A/B aggravates the levels of neurotransmitters such as dopamine, noradrenalin and serotonin which could relieves the symptoms of age related AD brain …”

Section: Introductionmentioning

confidence: 99%

Ethoxylated Head of Chalcones as a New Class of Multi‐Targeted MAO Inhibitors

et al. 2019

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A series of eleven ethoxysubstituted chalcones (E1-E11) were synthesized and investigated for their inhibitory potential towards human recombinant monoamine oxidase A and B (hMAOÀ A and hMAOÀ B, respectively) and acetylcholinesterase (AChE). IC 50 values of 4.63 � 0.15 and 0.053 � 0.003 μM were obtained for MAOÀ A and MAOÀ B, respectively, by the most interesting compound (2E)-1-(4-ethoxyphenyl)-3-(4-fluorophenyl)prop-2-en-1-one (E7), and it was characterized by a high selectivity index (SI = 87.4) for MAOÀ B. Inhibitions by E7 against MAOÀ A and MAOÀ B were recovered (75.9 and 74.5%, respectively) to near the levels of reversible references (77.1 and 77.4%, respectively). The inhibition modes of E7 for MAOÀ A and MAOÀ B were competitive with K i values of 2.65 � 0.064 and 0.011 � 0.0011 μM, respectively. Compounds (2E)-1-(4ethoxyphenyl)-3-(4-ethylphenyl) prop-2-en-1-one (E10) and (2E)-1-(4-ethoxyphenyl)-3-[4-(trifluoromethyl)phenyl]prop-2-en-1-one (E11) showed good inhibitions against AChE with IC 50 values of 2.86 � 0.041 and 3.23 � 0.0073 μM, respectively. A combined molecular docking/MM-GBSA approach was used that employed quantum mechanics (QM) partial charges; this technique revealed the molecular rationale behind the observed MAOÀ B selectivity for this molecular series. Taken together, these results indicate that E7 is a potent, selective and reversible competitive inhibitor of MAOÀ B with moderately potent AChE inhibitory activity that has potential as a multitargeting drug

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Section: Introductionmentioning

confidence: 99%

Ethoxylated Head of Chalcones as a New Class of Multi‐Targeted MAO Inhibitors

et al. 2019

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“…For the ChE inhibition experiments, we used the Ellman protocol [ 22 ], the cheap and easily available EeAChE and eqBuChE and tacrine as reference. As shown in Table 1 , only compound 3h had a percentage of inhibition against AChE at 10 mM higher than 50% and showed an IC 50 equal to 1.8 μM, only 60-fold less active than tacrine (IC 50 = 0.03 μM) [ 23 , 24 ]. However, five compounds 3c, 3h and 3k-l were active against BuChE with IC 50 ranging from 2.0 μM for 3h to 9.6 μM for 3k.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Hantzsch Adducts as Cholinesterases and Calcium Flux inhibitors, Antioxidants and Neuroprotectives

Angona¹,

Martin²,

Daniel³

et al. 2020

IJMS

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We report herein the design, synthesis, biological evaluation, and molecular modelling of new inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), able to block Ca+2 channels also showing antioxidant and neuroprotective activities. The new MTDL, dialkyl 2,6-dimethyl-4-(4-((5-aminoalkyl)oxy)phenyl)-1,4-dihydropyridine-3,5-dicarboxylate 3a-p, have been obtained via Hantzsch reaction from appropriate and commercially available precursors. Pertinent biological analysis has prompted us to identify MTDL 3h [dimethyl-4-(4-((5-(4-benzylpiperidin-1-yl)pentyl)oxy)phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate] as an attractive inhibitor of AChE (1.8 μM) and BuChE (2 μM), Ca+2 channel antagonist (47.72% at 10 μM), and antioxidant (2.54 TE) agent, showing significant neuroprotection 28.68% and 38.29% against H2O2, and O/R, respectively, at 0.3 μM, thus being considered a hit-compound for further investigation in our search for anti-Alzheimer’s disease agents.

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“…Inhibition of acetylcholinesterase (AChE), which catalyzes the degradation of acetylcholine, improves the cholinergic function, and is a target which represents an innovative therapeutic weapon for the treatment of AD . Studies reveal that selective MAO‐B inhibitors such as selegiline, rasagiline, and safinamide retard the further neurodegeneration and have a positive effect on memory modalities in AD . Recent in vivo studies in mice reported the correlation between the progress of AD and MAO activity .…”

Section: Introductionmentioning

confidence: 99%

Potent and highly selective dual‐targeting monoamine oxidase‐B inhibitors: Fluorinated chalcones of morpholine versus imidazole

Mathew

Baek

Parambi

et al. 2019

Archiv der Pharmazie

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Two series of fluorinated chalcones containing morpholine and imidazole-based compounds (f1-f8) were synthesized and evaluated for recombinant human monoamine oxidase (MAO)-A and -B as well as acetylcholinesterase inhibitory activities.Our results indicate that morpholine containing chalcones are highly selective MAO-B inhibitors having reversibility properties. All the imidazole-based fluorinated chalcones showed weak MAO inhibitions in both isoforms. Among the tested compounds, (2E)-3-(3-fluorophenyl)-1- [4-(morpholin-4-yl)phenyl]prop-2-en-1-one (f2) showed potent inhibitory activity for recombinant human MAO-B (IC 50 = 0.087 μM) with a high selectivity index (SI) of 517.2. In the recovery experiments using dialysis, the residual activity of MAO-B inhibited by f2 was close to that with the reversible reference inhibitor. Inhibition assays revealed that the K i values of f1 and f2 for MAO-B were 0.027 and 0.020 μM, respectively, with competitive patterns. All the morpholine-based compounds (f1-f4) showed moderate inhibition toward acetylcholinesterase with IC 50 values ranging between 24 and 54 μM. All morpholine-containing compounds exhibit good blood-brain barrier permeation in the PAMPA method. The rational approach regarding the highly selective MAO-B inhibitor f2 was further ascertained by induced fit docking and molecular dynamics simulation studies. K E Y W O R D S acetylcholinesterase, chalcone, entrance cavity, imidazole, MAO-B selective inhibitor, molecular dynamics, morpholine Parkinson's disease (PD) encompasses a multicentric progressive loss of specific neuronal cell populations resulting in the development of the movement disorder. PD is the second most prevalent age-related neurodegenerative disease that results from the loss of nigrostriatal dopaminergic neurons. [1] The neurodegeneration is initiated decades before it affects the motor function, and the phenotype is usually characterized by resting tremors, rigidity, and bradykinesia. [2] Monoamine oxidase (MAO; EC 1.4.3.4) has increased expression levels in neuronal tissues as well as gastro and hepatic tissues. [3] MAO-A and MAO-B inhibitors are in clinical use for the treatment of neurological and psychiatric disorders, respectively. [4] Biochemically, these two isoenzymes are differentiated by their substrate and inhibitor specificities. [5] Inhibition of isoform B, which is mainly localized in the raphe nucleus of serotonergic neuronal cell bodies, leads to elevated levels of dopamine (DA) in Parkinsonism patients. The phenomenal advances in neurochemistry have greatly helped in unfolding the pathophysiology of this disorder and provided the basis for the introduction of levodopa. The new understanding and disclosure of the mechanisms of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) in primate models has triggered a resurgence concerning the etiological factors that enhance the inhibition of MAO-B with deprenyl, the first MAO-B inhibitor which potentiates the effects of levodopa and prolongs the life of PD patients. [6]Most MAO-B inh...

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Dual Inhibitors of Cholinesterases and Monoamine Oxidases for Alzheimer’S Disease

Cited by 46 publications

References 119 publications

Ethoxylated Head of Chalcones as a New Class of Multi‐Targeted MAO Inhibitors

Ethoxylated Head of Chalcones as a New Class of Multi‐Targeted MAO Inhibitors

Synthesis of Hantzsch Adducts as Cholinesterases and Calcium Flux inhibitors, Antioxidants and Neuroprotectives

Potent and highly selective dual‐targeting monoamine oxidase‐B inhibitors: Fluorinated chalcones of morpholine versus imidazole

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