Design, synthesis, pharmacological evaluation, QSAR analysis, molecular modeling and ADMET of novel donepezil–indolyl hybrids as multipotent cholinesterase/monoamine oxidase inhibitors for the potential treatment of Alzheimer's disease

Bautista-Aguilera, Oscar M.; Esteban, Gerard; Bolea, Irène; Nikolic, Katarina; Agbaba, Danica; Moraleda, Ignacio; Iriepa, Isabel; Samadi, Abdelouahid; Soriano, Elena; Unzeta, Mercedes; Marco‐Contelles, José

doi:10.1016/j.ejmech.2013.12.028

Cited by 117 publications

(81 citation statements)

References 59 publications

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“…11, 19,21,22 However, they might have a negative influence in this treatment, if we consider that activation, instead of inhibition, of neuronal nAChRs, and especially of the α7 subtype, is actually explored as a possibility of therapeutic intervention in AD. 33 Nevertheless, the mechanism of action of α7 nAChRs on AD appears to be very complex, 34 since both neuroprotection 35 and neurotoxicity 36 may be influenced by α7 nAChR activity.…”

Section: Resultsmentioning

confidence: 99%

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N-Benzylpiperidine Derivatives as α7 Nicotinic Receptor Antagonists

Criado

Mulet

Sala

et al. 2016

ACS Chem. Neurosci.

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Upon the study of a series of less complex derivatives, the N-benzylpiperidine motif, common to these compounds, was found to be the main pharmacophoric group. Thus, 2-(1-benzylpiperidin-4-yl)-ethylamine (48) showed an inhibitory potency comparable to the one of the previous compounds and also a clear preference for α7 nAChRs. In a neuroblastoma cell line, representative compounds 13 and 48 also inhibited, in a concentration-dependent manner, cytosolic Ca 2+ signals mediated mainly by α7 nAChRs.Finally, these compounds, especially 38 and 13, inhibited 5-HT 3A serotonin receptors whereas they had no effect on α1 glycine receptors.

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Section: Resultsmentioning

confidence: 99%

“…12, [18][19][20][21][22] As in the case of ASS234, each compound was individually tested by co-application with ACh to α7 nAChRs. As shown in Figure 3, a varied degree of inhibitory responses of ACh-induced currents was observed, whereas no significant potentiation was exerted by any of the tested compounds.…”

Section: Resultsmentioning

confidence: 99%

N-Benzylpiperidine Derivatives as α7 Nicotinic Receptor Antagonists

Criado

Mulet

Sala

et al. 2016

ACS Chem. Neurosci.

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“…Therefore, multipotent brain permeable drugs affecting few brain targets involved in the disease pathology, such as MAO and ChE enzymes, Aβ generation/aggregation and iron accumulations were extensively studied as essential therapeutic approach in treatment of AD [28,[34][35][36][37][38][39][40][41][42][43]." Quantitative Structure Activity Relationship (QSAR) modeling and related cheminformatic methods are developed and applied in helping to guide computer-aideddrug-design (CADD) [44,45] and in polypharmacology for design of ligands with unique polypharmacological profiles [8,46].…”

Section: Polypharmacologymentioning

confidence: 99%

“…For example, the MAO A/B and AChE/BuChE inhibiting activities of multitarget donepezil and tacrine hybrids [35,38,39,40,42,43,47] were used in our recent 3D-QSAR and ASS234 optimisation studies [36,37]. [33].…”

Section: Polypharmacologymentioning

confidence: 99%

Polypharmacology of dopamine D1-like receptor antagonists

Nikolic¹,

Filipić²,

Agbaba³

2015

Arh farmaciju

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Drug discovery based on development of selective ligands for a specific target intended to modulate its activity and revert pathophysiological process is now recognized as too simplistic to design effective agent for complex multifactorial diseases, characterized by diverse physiological dysfunctions caused by deregulations of complex networks of proteins. Major challenge in modern drug discovery is to rationally design multitarget drugs able to specifically modulate only a group of desired targets while minimizing interactions with off-targets. Multifactorial cerebral mechanisms implicated in mental (psychiatrics) and neurodegenerative diseases and interactions of the neurotransmitter systems are two main reasons for applying polypharmacology ("multi-target") strategy in drug discovery for these complex brain diseases. In this paper we review polypharmacological profile and potential therapeutic application of dopamine D 1 -like receptor antagonists.

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“…In detail, scaffolds containing a propargylamine moiety are of particular interest due to their reported beneficial actions 18,19 . In a previous work we have demonstrated that the concurrent inhibition of this enzyme and the binding to the 5-HT3 receptor can lead to interesting compounds 20 .…”

Section: Introductionmentioning

confidence: 99%

(Thiazol-2-yl)hydrazone derivatives from acetylpyridines as dual inhibitors of MAO and AChE: synthesis, biological evaluation and molecular modeling studies

D’Ascenzio

Chimenti

Gidaro

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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Department of Pharmacy, ''G. D'Annunzio'' University of Chieti-Pescara, Chieti Scalo (CH), Italy Abstract Several (thiazol-2-yl)hydrazone derivatives from 2-, 3-and 4-acetylpyridine were synthesized and tested against human monoamine oxidase (hMAO) A and B enzymes. Most of them had an inhibitory effect in the low micromolar/high nanomolar range, being derivatives of 4-acetylpyridine selective hMAO-B inhibitors also at low nanomolar concentrations. The structure-activity relationship, as confirmed by molecular modeling studies, proved that the pyridine ring linked to the hydrazonic nitrogen and the substituted aryl moiety at C4 of the thiazole conferred the inhibitory effects on hMAO enzymes. Successively, the strongest hMAO-B inhibitors were tested toward acetylcholinesterase (AChE) and the most interesting compound showed activity in the low micromolar range. Our results suggest that this scaffold could be further investigated for its potential multi-targeted role in the discovery of new drugs against the neurodegenerative diseases.

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Design, synthesis, pharmacological evaluation, QSAR analysis, molecular modeling and ADMET of novel donepezil–indolyl hybrids as multipotent cholinesterase/monoamine oxidase inhibitors for the potential treatment of Alzheimer's disease

Cited by 117 publications

References 59 publications

N-Benzylpiperidine Derivatives as α7 Nicotinic Receptor Antagonists

N-Benzylpiperidine Derivatives as α7 Nicotinic Receptor Antagonists

Polypharmacology of dopamine D1-like receptor antagonists

(Thiazol-2-yl)hydrazone derivatives from acetylpyridines as dual inhibitors of MAO and AChE: synthesis, biological evaluation and molecular modeling studies

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