- Synthesis, biological evaluation and molecular modeling studies of phthalazin-1(2: H)-one derivatives as novel cholinesterase inhibitors
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A new series of donepezil analogues based on the phthalazin-1(2H)-one scaffold was designed and synthesized with the aim of exploring its potential as human ChEIs. Biological results revealed that the structural modifications proposed significantly affected ChE inhibitory potency as well as selectivity for AChE/BuChE. Compound 1d showed promising in vitro inhibition of both enzymes in the μM range. However, most target compounds were significantly more active against AChE than BuChE, specifically 1f, 1h and 1j, with IC50 values in the low micromolar or submicromolar range, the most active compounds in the series. Docking simulations suggested that the most active compounds can recognize the donepezil binding site using a similar interactions network. These results allowed us to rationalize the observed structure-activity relationships. Moreover, the predicted physicochemical and ADME properties were also comparable to those of donepezil.
- Vila, Noemí,Besada, Pedro,Vi?a, Dolores,Sturlese, Mattia,Moro, Stefano,Terán, Carmen
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- N-methyl-N-((1-methyl-5-(3-(1-(2-methylbenzyl)piperidin-4-yl)propoxy)-1H-indol-2-yl)methyl)prop-2-yn-1-amine, a new cholinesterase and monoamine oxidase dual inhibitor
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On the basis of N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)-N-methylprop-2-yn-1-amine (II, ASS234) and QSAR predictions, in this work we have designed, synthesized, and evaluated a number of new indole derivatives from which we have identified N-methyl-N-((1-methyl-5-(3-(1-(2-methylbenzyl)piperidin-4-yl)propoxy)-1H-indol-2-yl)methyl)prop-2-yn-1-amine (2, MBA236) as a new cholinesterase and monoamine oxidase dual inhibitor.
- Bautista-Aguilera, Oscar M.,Samadi, Abdelouahid,Chioua, Mourad,Nikolic, Katarina,Filipic, Slavica,Agbaba, Danica,Soriano, Elena,De Andrés, Lucía,Rodríguez-Franco, María Isabel,Alcaro, Stefano,Ramsay, Rona R.,Ortuso, Francesco,Ya?ez, Matilde,Marco-Contelles, José
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- Donepezil–melatonin hybrids as butyrylcholinesterase inhibitors: Improving binding affinity through varying mode of linking fragments
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Hybrid inhibitors of acetyl- and butyrylcholinesterase are compounds that combine structural motifs of two different classical inhibitors, leading to a dual binding ligand. A rapidly growing collection of those compounds involves a wide diversity of structural motifs, but the way of linking two active fragments and its impact on the affinity toward cholinesterases usually remains beyond the extent of investigation. We present hereby a detailed analysis of this aspect using melatonin–donepezil hybrids. A new series of compounds, in which two fragments are connected using a carbamate linker, exhibits excellent activity and selectivity toward butyrylcholinesterase.
- ?ozińska, Iwona,?wierczyńska, Aleksandra,Mol?da, Zuzanna,Hartman, Alwin M.,Hirsch, Anna K. H.,Czarnocki, Zbigniew
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- M2 Subtype preferring dibenzodiazepinone-type muscarinic receptor ligands: Effect of chemical homo-dimerization on orthosteric (and allosteric?) binding
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A series of new dibenzodiazepinone-type muscarinic receptor ligands, including two homo-dimeric compounds, was prepared. Sixteen representative compounds were characterized in equilibrium binding studies with [3H]N-methylscopolamine ([3H]NMS) at the muscarinic receptor subtype M2, and seven selected compounds were additionally investigated at M1, M3, M4 and M5 with respect to receptor subtype selectivity. The side chain of the known M2 preferring muscarinic receptor antagonist DIBA was widely varied with respect to chain length and type of the basic group (amine, imidazole, guanidine and piperazine). Most of the structural changes were well tolerated with respect to muscarinic receptor binding, determined by displacement of [3H]NMS. Compounds investigated at all subtypes shared a similar selectivity profile, which can be summarized as M2 > M1 ≈ M4 > M3 ≈ M5 (46, 50, 57, 62-64) and M2 > M1 ≈ M4 > M3 > M5 (1, 58). The homo-dimeric dibenzodiazepinone derivatives UNSW-MK250 (63) and UNSW-MK262 (64) exhibited the highest M2 receptor affinities (pIC50 = 9.0 and 9.2, respectively). At the M2 receptor a steep curve slope of -2 was found for the dimeric ligand 63, which cannot be described according to the law of mass action, suggesting a more complex mechanism of binding. In addition to equilibrium binding studies, for selected ligands, we determined pEC50,diss, an estimate of affinity to the allosteric site of M2 receptors occupied with [3H]NMS. Compounds 58 and 62-64 were capable of retarding [3H]NMS dissociation by a factor >10 (Emax,diss >92%), with highest potency (pEC50,diss = 5.56) residing in the dimeric compound 64. As the monomeric counterpart of 64 was 100 times less potent (62: pEC50,diss = 3.59), these data suggest that chemical dimerization of dibenzodiazepinone-type M receptor ligands can enhance allosteric binding.
- Keller, Max,Tr?nkle, Christian,She, Xueke,Pegoli, Andrea,Bernhardt, Günther,Buschauer, Armin,Read, Roger W.
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p. 3970 - 3990
(2015/02/19)
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- Synthesis, biological evaluation, and molecular modeling of donepezil and N-[(5-(Benzyloxy)-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine hybrids as new multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer's disease
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A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B, has been synthesized. Novel compounds (3-9) have been designed using a conjunctive approach that combines the benzylpiperidine moiety of the AChE inhibitor donepezil (1) and the indolyl propargylamino moiety of the MAO inhibitor N-[(5-benzyloxy-1-methyl-1H-indol-2- yl)methyl]-N-methylprop-2-yn-1-amine (2), connected through an oligomethylene linker. The most promising hybrid (5) is a potent inhibitor of both MAO-A (IC50 = 5.2 ± 1.1 nM) and MAO-B (IC50 = 43 ± 8.0 nM) and is a moderately potent inhibitor of AChE (IC50 = 0.35 ± 0.01 μM) and BuChE (IC50 = 0.46 ± 0.06 μM). Moreover, molecular modeling and kinetic studies support the dual binding site to AChE, which explains the inhibitory effect exerted on Aβ aggregation. Overall, the results suggest that the new compounds are promising multitarget drug candidates with potential impact for Alzheimer's disease therapy. (Figure presented)
- Bolea, Irene,Juárez-Jiménez, Jordi,De Los Ríos, Cristóbal,Chioua, Mourad,Pouplana, Ramón,Luque, F. Javier,Unzeta, Mercedes,Marco-Contelles, José,Samadi, Abdelouahid
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p. 8251 - 8270
(2012/02/14)
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- Potent 1,3,4-trisubstituted pyrrolidine CCR5 receptor antagonists: Effects of fused heterocycles on antiviral activity and pharmacokinetic properties
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A series of 1,3,4-trisubstituted pyrrolidine CCR5 receptor antagonists containing a variety of fused heterocycles at the 4-position of the piperidine side chain has been discovered, which are orally bioavailable with potent anti-HIV activity.
- Kim, Dooseop,Wang, Liping,Hale, Jeffrey J.,Lynch, Christopher L.,Budhu, Richard J.,MacCoss, Malcolm,Mills, Sander G.,Malkowitz, Lorraine,Gould, Sandra L.,Demartino, Julie A.,Springer, Martin S.,Hazuda, Daria,Miller, Michael,Kessler, Joseph,Hrin, Renee C.,Carver, Gwen,Carella, Anthony,Henry, Karen,Lineberger, Janet,Schleif, William A.,Emini, Emilio A.
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p. 2129 - 2134
(2007/10/03)
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- Synthesis and Structure-Activity Relationships of Conformationally Constrained Histamine H3 Receptor Agonists
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Immepip, a conformationally constrained analogue of the histamine congener imbutamine, shows high affinity and functional activity on the human H 3 receptor. Using histamine and its homologues as prototypes, other rigid analogues containing eit
- Kitbunnadaj, Ruengwit,Zuiderveld, Obbe P.,De Esch, Iwan J. P.,Vollinga, Roeland C.,Bakker, Remko,Lutz, Martin,Spek, Anthony L.,Cavoy, Emile,Deltent, Marie-France,Menge, Wiro M. P. B.,Timmerman, Henk,Leurs, Rob
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p. 5445 - 5457
(2007/10/03)
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- Synthetic study of 4-substituted piperidine ring in elarofiban, RWJ-50042, tirofiban and paroxetine
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A new strategy for synthesizing a 4-substituted piperidine ring uses the formal [3+3] cycloaddition reaction as the key protocol. This method provides a convenient formal synthesis of elarofiban, RWJ-50042, tirofiban and paroxetine.
- Chang, Meng-Yang,Lin, John Yi-Chung,Chen, Shui-Tein,Chang, Nein-Chen
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p. 1079 - 1088
(2007/10/03)
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- Pyrrolidine modulators of chemokine receptor activity
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The present invention is directed to pyrrolidine compounds of the formula 1: (wherein R1, R2, R3, R4, R5, R6and n are defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors CCR-5 and/or CCR-3.
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- Novel pyridazinamine derivatives
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Novel pyridazinamine derivatives having antiviral activity, compositions containing these compounds as active ingredient, and a method of destructing viruses or preventing the growth thereof in warm-blooded animals suffering from diseases caused by these viruses. Processes for preparing said compounds and compositions.
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