1-N-Substituted thiocarbamoyl-3-phenyl-5-thienyl-2-pyrazolines: A novel cholinesterase and selective monoamine oxidase B inhibitors for the treatment of Parkinson's and Alzheimer's diseases

Uçar, Gülberk; Gökhan, Nesrın; Yesilada, A.; Bilgin, A. Altan

doi:10.1016/j.neulet.2005.03.028

Cited by 81 publications

(53 citation statements)

References 18 publications

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“…There are precedents in which an allosteric inhibitor irreversibly destabilizes an enzyme via a nonoxidative mechanism (Piver et al, 2001;Ucar et al, 2005;Domínguez et al, 2012).…”

Section: Selective Inhibitors Of Cd45 Ptpmentioning

confidence: 99%

Allosteric Noncompetitive Small Molecule Selective Inhibitors of CD45 Tyrosine Phosphatase Suppress T-Cell Receptor Signals and Inflammation In Vivo

et al. 2014

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CD45 is a receptor-like member of the protein tyrosine phosphatase (PTP) family. We screened in silico for small molecules binding at a predicted allosteric pocket unique to the CD45 intracellular domain, and validated inhibitors by in vitro phosphatase assays. Compound 211 exhibited a CD45 IC 50 value of 200 nM and had .100-fold selectivity over six related PTPs. The relevance of the allosteric pocket was verified through site-directed mutagenesis. Compound 211 has a noncompetitive mechanism of action, and it is extremely effective at preventing dephosphorylation of substrate Lck phosphotyrosine (pY)-505 versus preventing dephosphorylation of Lck pY-393. In cultured primary T cells, compound 211 prevents T-cell receptor-mediated activation of Lck, Zap-70, and mitogen-activated protein kinase, and interleukin-2 production. In a delayed-type hypersensitivity reaction in vivo, compound 211 abolished inflammation. This work demonstrates a novel approach to develop effective allosteric inhibitors that can be expanded to target the corresponding allosteric domains of other receptor PTPs.

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“…There are precedents in which an allosteric inhibitor irreversibly destabilizes an enzyme via a nonoxidative mechanism (Piver et al, 2001;Ucar et al, 2005;Domínguez et al, 2012).…”

Section: Selective Inhibitors Of Cd45 Ptpmentioning

confidence: 99%

Allosteric Noncompetitive Small Molecule Selective Inhibitors of CD45 Tyrosine Phosphatase Suppress T-Cell Receptor Signals and Inflammation In Vivo

et al. 2014

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“…In Figure 5 we can see that the retrodonor process is due to the C3, C4, C6, C8, O12, and N30 atoms for regions ( − ) (Figure 5(a)) and C2, C3, C5, C6, C7, C8, and N30 atoms for regions ( + ) (Figure 5(b)) for the more active molecule 5 that causes one electronic donation capacity quantified by the electrophilicity index (see Table 7) which allows the stabilization in the active site and postulate the retrodonor process by the C3, C6, C8, and CN30 ( Figure 5(a)) atoms. However the molecular set studied is hybrid molecules that act as MAO-B inhibitors by virtue of the covalent bond formed by the propargylamino moiety with the Flavin Adenine Dinucleotide (FAD) cofactor and as ChE inhibitors by interaction at the catalytic site with the N-benzyl-cycloalkylamino moiety and at the peripheral site (PAS of AChE) with the heteroaromatic moiety [13,[75][76][77][78][79][80][81]. Therefore, retrodonation on the central ring might even take place but as an additional interaction.…”

Section: Resultsmentioning

confidence: 99%

Scale Alpha and Beta of Quantitative Convergence and Chemical Reactivity Analysis in Dual Cholinesterase/Monoamine Oxidase Inhibitors for the Alzheimer Disease Treatment Using Density Functional Theory (DFT)

Morales-Bayuelo

Baldiris

Vivas‐Reyes

2013

Journal of Theoretical Chemistry

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Molecular quantum similarity descriptors and Density Functional Theory (DFT) based reactivity descriptors were studied for a series of cholinesterase/monoamine oxidase inhibitors used for the Alzheimer's disease treatment (AD). This theoretical study is expected to shed some light onto some molecular aspects that could contribute to the knowledge of the molecular mechanics behind interactions of these molecules with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamine oxidase (MAO) A and B. The Topogeometrical Superposition Algorithm to handle flexible molecules (TGSA-Flex) alignment method was used to solve the problem of the relative orientation in the quantum similarity (QS) field. Using the molecular quantum similarity (MQS) field and reactivity descriptors supported in the DFT was possible the quantification of the steric and electrostatic effects through of the Coulomb and Overlap quantitative convergence scales (alpha and beta). In addition, an analysis of reactivity indexes is development, using global and local descriptors, identifying the binding sites and selectivity in the (cholinesterase/monoamine oxidase) inhibitors, understanding the retrodonor process, and showing new insight for drugs design in a disease of difficult control as Alzheimer.

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“…metabolites of mangrove fungus Xylaria sp. [11] Dual AChE and MAO inhibitors Coumarin derivatives, [12] 1-N-substituted thiocarbamoyl-3-phenyl-5-thienyl-2-pyrazoline derivatives, [13] xanthones [14] Dual AChE and serotonin transporter inhibitors (S)-2j (RS-1259) [15] Dual binding site AChE inhibitors AP2238, [16] tacrine-thiadiazolidinone hybrids [17] Dual AChE and Abeta aggregation inhibitors Propidium-tacrine heterodimer, [18] tacripyrines (tacrine-dihydropyridine hybrids obtained by combining tacrine with nimodipine), [19] Congo red dye, [20] huperzine A (HupA)-based bivalent ligands [21] Dual AChE and NMDA inhibitors Bis (7)-tacrine, i.e. (1,7-N-heptylene-bis-9,9′-amino-1,2,3,4-tetrahydroacridine) [22] Dual AChE and b-secretase (BACE) inhibitors [23] Dual acetylcholinesterase inhibitors and antioxidants PMS777 [24] Psychosis Dual cAMP and cGMP phosphodiesterase 10A (PDE10A) inhibitors…”

Section: Dual Cholinesterase Inhibitorsmentioning

confidence: 99%

Dual inhibition: a novel promising pharmacological approach for different disease conditions

Patyar

Prakash

Medhi

2011

Journal of Pharmacy and Pharmacology

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To overcome the problems associated with polypharmacy, which include medication non compliance, adverse drug reactions, drug-drug interactions and increased pill-burden, various strategies, such as sustained-release drugs and fixed-dose combination regimens (polypills), have been developed. Out of these, a novel and very much promising approach is the use of dual-action drugs. Amongst the dual-action drugs, there is a class of compounds known as dual inhibitors, which possess the dual inhibitory activity. The most common examples of dual inhibitors are rivastigmine, ladostigil, asenapine, phenserine, amitriptyline, clomipramine, doxepin and desipramine. This review article focuses on the conventional drugs used in different diseases which possess dual inhibition activity as well as those which are still in the preclinical/clinical phase.

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1-N-Substituted thiocarbamoyl-3-phenyl-5-thienyl-2-pyrazolines: A novel cholinesterase and selective monoamine oxidase B inhibitors for the treatment of Parkinson's and Alzheimer's diseases

Cited by 81 publications

References 18 publications

Allosteric Noncompetitive Small Molecule Selective Inhibitors of CD45 Tyrosine Phosphatase Suppress T-Cell Receptor Signals and Inflammation In Vivo

Allosteric Noncompetitive Small Molecule Selective Inhibitors of CD45 Tyrosine Phosphatase Suppress T-Cell Receptor Signals and Inflammation In Vivo

Scale Alpha and Beta of Quantitative Convergence and Chemical Reactivity Analysis in Dual Cholinesterase/Monoamine Oxidase Inhibitors for the Alzheimer Disease Treatment Using Density Functional Theory (DFT)

Dual inhibition: a novel promising pharmacological approach for different disease conditions

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