Dual functional cholinesterase and MAO inhibitors for the treatment of Alzheimer’s disease: synthesis, pharmacological analysis and molecular modeling of homoisoflavonoid derivatives

Wang, Yali; Sun, Yang; Guo, Yueyan; Wang, Zechen; Huang, Ling; Li, Xingshu

doi:10.3109/14756366.2015.1024675

Cited by 25 publications

(24 citation statements)

References 42 publications

(45 reference statements)

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“…Some available drugs present the capability to modulate more than one bioreceptor, as exemplified by the atypical antipsychotics olanzapine, risperidone and aripiprazole, which act mainly as dopamine and serotonin receptor antagonists and have lower affinity to histamine, cholinergic muscarinic and α-adrenergic receptors [ 5 ]. Ladostigil is another example of dual monoamine oxidase B (MAO-B) and acetylcholine esterase (AChE) inhibitor [ 6 ] ( Figure 1 ). Despite their great promise in the clinical application, any potential risk of side effects should not be neglected.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological and Toxicological Screening of Novel Benzimidazole-Morpholine Derivatives as Dual-Acting Inhibitors

et al. 2017

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The aim of this study was to investigate acetylcholinesterase (AChE), monoamine oxidase A (MAO-A), monoamine oxidase B (MAO-B), cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzyme inhibitory, and antimicrobial activities of a new series of 2-(4-substituted phenyl)-1-[2-(morpholin-4-yl)ethyl]-1H-benzimidazole derivatives, for their possible use as multi-action therapeutic agents. Target compounds (n = 15) were synthesized under microwave irradiation conditions in two steps, and their structures were elucidated by FT-IR, 1H-NMR, 13C-NMR and high resolution mass spectroscopic analyses. Pharmacological screening studies revealed that two of the compounds (2b and 2j) have inhibitory potential on both COX-1 and COX-2 enzymes. In addition, cytotoxic and genotoxic properties of the compounds 2b, 2j and 2m were investigated via the well-known MTT and Ames tests, which revealed that the mentioned compounds are non-cytotoxic and non-genotoxic. As a concise conclusion, two novel compounds were characterized as potential candidates for treatment of frequently encountered inflammatory diseases.

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Section: Introductionmentioning

confidence: 99%

Pharmacological and Toxicological Screening of Novel Benzimidazole-Morpholine Derivatives as Dual-Acting Inhibitors

et al. 2017

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“…Therefore, MAO-B inhibitors have been used as drugs to induce dopamine levels [19]. It is suggested that some MAO-B inhibitors have a potential as therapeutic or preventive treatment for dementia including Alzheimer’s disease [20,21]. We also showed that the administration of WY dipeptide increased total dopamine levels in the hippocampus and frontal cortex.…”

Section: Discussionmentioning

confidence: 77%

Tryptophan-Tyrosine Dipeptide, the Core Sequence of β-Lactolin, Improves Memory by Modulating the Dopamine System

et al. 2019

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Tryptophan-tyrosine (WY)-related peptides including the β-lactopeptide of the glycine-threonine-tryptophan-tyrosine peptide, β-lactolin, improve spatial memory. However, whether and how the WY dipeptide as the core sequence in WY-related peptides improves memory functions has not been investigated. This study assessed the pharmacological effects of the WY dipeptide on memory impairment to elucidate the mechanisms. Here, we showed that oral administration of dipeptides of WY, tryptophan-methionine (WM), tryptophan-valine, tryptophan-leucine, and tryptophan-phenylalanine improved spontaneous alternation of the Y-maze test in scopolamine-induced amnesic mice. In contrast, tyrosine-tryptophan, methionine-tryptophan, tryptophan, tyrosine, and methionine had no effect. These results indicated that the conformation of dipeptides with N-terminal tryptophan is required for their memory improving effects. WY dipeptide inhibited the monoamine oxidase B activity in vitro and increased dopamine levels in the hippocampus and frontal cortex, whereas tryptophan did not cause these effects. In addition, the treatment with SCH-23390, a dopamine D1-like receptor antagonist, and the knockdown of the hippocampal dopamine D1 receptor partially attenuated the memory improvement induced by the WY dipeptide. Importantly, WY dipeptide improved the spontaneous alternations of the Y-maze test in aged mice. These results suggest that the WY dipeptide restores memory impairments by augmenting dopaminergic activity. The development of supplements rich in these peptides might help to prevent age-related cognitive decline.

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“…The inhibitory activities against AChE (from electric eel ) and BuChE (from equine serum ) were measured by the Ellman’s method . Rivastigmine and donepezil were used as the reference compounds. , The results are summarized in Table .…”

Section: Resultsmentioning

confidence: 99%

Discovery of Novel Pyrazolopyrimidinone Derivatives as Phosphodiesterase 9A Inhibitors Capable of Inhibiting Butyrylcholinesterase for Treatment of Alzheimer’s Disease

Huang

Zhang

et al. 2017

ACS Chem. Neurosci.

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Discovery of multitarget-directed ligands (MTDLs), targeting different factors simultaneously to control the complicated pathogenesis of Alzheimer's disease (AD), has become an important research area in recent years. Both phosphodiesterase 9A (PDE9A) and butyrylcholinesterase (BuChE) inhibitors could participate in different processes of AD to attenuate neuronal injuries and improve cognitive impairments. However, research on MTDLs combining the inhibition of PDE9A and BuChE simultaneously has not been reported yet. In this study, a series of novel pyrazolopyrimidinone-rivastigmine hybrids were designed, synthesized, and evaluated in vitro. Most compounds exhibited remarkable inhibitory activities against both PDE9A and BuChE. Compounds 6c and 6f showed the best IC values against PDE9A (6c, 14 nM; 6f, 17 nM) together with the considerable inhibition against BuChE (IC, 6c, 3.3 μM; 6f, 0.97 μM). Their inhibitory potencies against BuChE were even higher than the anti-AD drug rivastigmine. It is worthy mentioning that both showed moderate selectivity for BuChE over acetylcholinesterase (AChE). Molecular docking studies revealed their binding patterns and explained the influence of configuration and substitutions on the inhibition of PDE9A and BuChE. Furthermore, compounds 6c and 6f exhibited negligible toxicity, which made them suitable for the further study of AD in vivo.

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Dual functional cholinesterase and MAO inhibitors for the treatment of Alzheimer’s disease: synthesis, pharmacological analysis and molecular modeling of homoisoflavonoid derivatives

Cited by 25 publications

References 42 publications

Pharmacological and Toxicological Screening of Novel Benzimidazole-Morpholine Derivatives as Dual-Acting Inhibitors

Pharmacological and Toxicological Screening of Novel Benzimidazole-Morpholine Derivatives as Dual-Acting Inhibitors

Tryptophan-Tyrosine Dipeptide, the Core Sequence of β-Lactolin, Improves Memory by Modulating the Dopamine System

Discovery of Novel Pyrazolopyrimidinone Derivatives as Phosphodiesterase 9A Inhibitors Capable of Inhibiting Butyrylcholinesterase for Treatment of Alzheimer’s Disease

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