Base de dados : MEDLINE
Pesquisa : D03.633.300.046.250.900 [Categoria DeCS]
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[PMID]:29268129
[Au] Autor:Cen J; Guo H; Hong C; Lv J; Yang Y; Wang T; Fang D; Luo W; Wang C
[Ad] Endereço:Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng 475004, China.
[Ti] Título:Development of tacrine-bifendate conjugates with improved cholinesterase inhibitory and pro-cognitive efficacy and reduced hepatotoxicity.
[So] Source:Eur J Med Chem;144:128-136, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:A novel series of tacrine-bifendate (THA-DDB) conjugates (7a-e) were synthesized and evaluated as potential anti-Alzheimer's agents. These compounds showed potent cholinesterase and self-induced ß-amyloid (Aß) aggregation inhibitory activities. A Lineweaver-Burk plot and molecular modeling study showed that these compounds can target both catalytic active site (CAS) and peripheral anionic site (PAS) of acetylcholinesterase (AChE). The cytotoxicity of the conjugate 7d against PC12 and HepG2 cells and hepatotoxicity against human hepatocyte cell line (HL-7702) were found to be considerably less compared to THA. Moreover, treatment with 7d did not exhibit significant hepatotoxicity in mice. Finally, in vivo studies confirmed that 7d significantly ameliorates the cognitive performances of scopolamine-treated ICR mice. Therefore, 7d has high potential for the treatment of Alzheimer's disease and warrants further investigation.
[Mh] Termos MeSH primário: Compostos de Bifenilo/química
Compostos de Bifenilo/farmacologia
Inibidores da Colinesterase/química
Inibidores da Colinesterase/farmacologia
Cognição/efeitos dos fármacos
Tacrina/análogos & derivados
Tacrina/farmacologia
[Mh] Termos MeSH secundário: Acetilcolinesterase/metabolismo
Doença de Alzheimer/tratamento farmacológico
Doença de Alzheimer/patologia
Animais
Compostos de Bifenilo/toxicidade
Linhagem Celular
Doença Hepática Induzida por Substâncias e Drogas/etiologia
Doença Hepática Induzida por Substâncias e Drogas/patologia
Inibidores da Colinesterase/toxicidade
Colinesterases/metabolismo
Desenho de Drogas
Células Hep G2
Seres Humanos
Fígado/efeitos dos fármacos
Fígado/patologia
Masculino
Camundongos Endogâmicos ICR
Células PC12
Ratos
Tacrina/toxicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biphenyl Compounds); 0 (Cholinesterase Inhibitors); 0G32E321W1 (bifendate); 4VX7YNB537 (Tacrine); EC 3.1.1.7 (Acetylcholinesterase); EC 3.1.1.8 (Cholinesterases)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171222
[St] Status:MEDLINE


  2 / 1615 MEDLINE  
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[PMID]:29405075
[Au] Autor:Zhu J; Yang H; Chen Y; Lin H; Li Q; Mo J; Bian Y; Pei Y; Sun H
[Ad] Endereço:a Department of Medicinal Chemistry , China Pharmaceutical University , Nanjing , China.
[Ti] Título:Synthesis, pharmacology and molecular docking on multifunctional tacrine-ferulic acid hybrids as cholinesterase inhibitors against Alzheimer's disease.
[So] Source:J Enzyme Inhib Med Chem;33(1):496-506, 2018 Dec.
[Is] ISSN:1475-6374
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The cholinergic hypothesis has long been a "polar star" in drug discovery for Alzheimer's disease (AD), resulting in many small molecules and biological drug candidates. Most of the drugs marketed for AD are cholinergic. Herein, we report our efforts in the discovery of cholinesterases inhibitors (ChEIs) as multi-target-directed ligands. A series of tacrine-ferulic acid hybrids have been designed and synthesised. All these compounds showed potent acetyl-(AChE) and butyryl cholinesterase(BuChE) inhibition. Among them, the optimal compound 10g, was the most potent inhibitor against AChE (electrophorus electricus (eeAChE) half maximal inhibitory concentration (IC ) = 37.02 nM), it was also a strong inhibitor against BuChE (equine serum (eqBuChE) IC = 101.40 nM). Besides, it inhibited amyloid ß-protein self-aggregation by 65.49% at 25 µM. In subsequent in vivo scopolamine-induced AD models, compound 10g obviously ameliorated the cognition impairment and showed preliminary safety in hepatotoxicity evaluation. These data suggest compound 10g as a promising multifunctional agent in the drug discovery process against AD.
[Mh] Termos MeSH primário: Doença de Alzheimer/tratamento farmacológico
Inibidores da Colinesterase/síntese química
Inibidores da Colinesterase/farmacologia
Ácidos Cumáricos/farmacologia
Simulação de Acoplamento Molecular
Tacrina/farmacologia
[Mh] Termos MeSH secundário: Acetilcolinesterase/metabolismo
Doença de Alzheimer/induzido quimicamente
Peptídeos beta-Amiloides/antagonistas & inibidores
Animais
Butirilcolinesterase/metabolismo
Inibidores da Colinesterase/química
Ácidos Cumáricos/química
Relação Dose-Resposta a Droga
Electrophorus
Cavalos
Seres Humanos
Ligantes
Masculino
Camundongos
Camundongos Endogâmicos ICR
Estrutura Molecular
Fragmentos de Peptídeos/antagonistas & inibidores
Agregados Proteicos/efeitos dos fármacos
Hidrobrometo de Escopolamina
Relação Estrutura-Atividade
Tacrina/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amyloid beta-Peptides); 0 (Cholinesterase Inhibitors); 0 (Coumaric Acids); 0 (Ligands); 0 (Peptide Fragments); 0 (Protein Aggregates); 0 (amyloid beta-protein (1-42)); 451IFR0GXB (Scopolamine Hydrobromide); 4VX7YNB537 (Tacrine); AVM951ZWST (ferulic acid); EC 3.1.1.7 (Acetylcholinesterase); EC 3.1.1.8 (Butyrylcholinesterase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180213
[Lr] Data última revisão:
180213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180207
[St] Status:MEDLINE
[do] DOI:10.1080/14756366.2018.1430691


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[PMID]:29278947
[Au] Autor:Chen Y; Zhu J; Mo J; Yang H; Jiang X; Lin H; Gu K; Pei Y; Wu L; Tan R; Hou J; Chen J; Lv Y; Bian Y; Sun H
[Ad] Endereço:a School of Pharmacy , Nanjing University of Chinese Medicine , Nanjing , China.
[Ti] Título:Synthesis and bioevaluation of new tacrine-cinnamic acid hybrids as cholinesterase inhibitors against Alzheimer's disease.
[So] Source:J Enzyme Inhib Med Chem;33(1):290-302, 2018 Dec.
[Is] ISSN:1475-6374
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Small molecule cholinesterases inhibitor (ChEI) provides an effective therapeutic strategy to treat Alzheimer's disease (AD). Currently, the discovery of new ChEI with multi-target effect is still of great importance. Herein, we report the synthesis, structure-activity relationship study and biological evaluation of a series of tacrine-cinnamic acid hybrids as new ChEIs. All target compounds are evaluated for their in vitro cholinesterase inhibitory activities. The representatives which show potent activity on cholinesterase, are evaluated for the amyloid ß-protein self-aggregation inhibition and in vivo assays. The optimal compound 19, 27, and 30 (human AChE IC = 10.2 ± 1.2, 16.5 ± 1.7, and 15.3 ± 1.8 nM, respectively) show good performance in ameliorating the scopolamine-induced cognition impairment and preliminary safety in hepatotoxicity evaluation. These compounds deserve further evaluation for the development of new therapeutic agents against AD.
[Mh] Termos MeSH primário: Doença de Alzheimer/tratamento farmacológico
Inibidores da Colinesterase/farmacologia
Cinamatos/farmacologia
Tacrina/farmacologia
[Mh] Termos MeSH secundário: Acetilcolinesterase/metabolismo
Doença de Alzheimer/metabolismo
Peptídeos beta-Amiloides/antagonistas & inibidores
Peptídeos beta-Amiloides/metabolismo
Animais
Butirilcolinesterase/metabolismo
Inibidores da Colinesterase/síntese química
Inibidores da Colinesterase/química
Cinamatos/química
Relação Dose-Resposta a Droga
Electrophorus
Cavalos
Seres Humanos
Masculino
Camundongos
Camundongos Endogâmicos ICR
Modelos Moleculares
Estrutura Molecular
Agregados Proteicos/efeitos dos fármacos
Relação Estrutura-Atividade
Tacrina/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amyloid beta-Peptides); 0 (Cholinesterase Inhibitors); 0 (Cinnamates); 0 (Protein Aggregates); 4VX7YNB537 (Tacrine); EC 3.1.1.7 (Acetylcholinesterase); EC 3.1.1.8 (Butyrylcholinesterase); U14A832J8D (cinnamic acid)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180105
[Lr] Data última revisão:
180105
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171228
[St] Status:MEDLINE
[do] DOI:10.1080/14756366.2017.1412314


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[PMID]:28925729
[Au] Autor:Panek D; Wichur T; Godyn J; Pasieka A; Malawska B
[Ad] Endereço:Department of Physicochemical Drug Analysis, Chair of Pharmaceutical Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Kraków, Medyczna 9, Poland.
[Ti] Título:Advances toward multifunctional cholinesterase and ß-amyloid aggregation inhibitors.
[So] Source:Future Med Chem;9(15):1835-1854, 2017 Oct.
[Is] ISSN:1756-8927
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The emergence of a multitarget design approach in the development of new potential anti-Alzheimer's disease agents has resulted in the discovery of many multifunctional compounds focusing on various targets. Among them the largest group comprises inhibitors of both cholinesterases, with additional anti-ß-amyloid aggregation activity. This review describes recent advances in this research area and presents the most interesting compounds reported over a 2-year span (2015-2016). The majority of hybrids possess heterodimeric structures obtained by linking structurally active fragments interacting with different targets. Multipotent cholinesterase inhibitors with ß-amyloid antiaggregating activity may additionally possess antioxidative, neuroprotective or metal-chelating properties or less common features such as anti-ß-secretase or τ-antiaggregation activity.
[Mh] Termos MeSH primário: Peptídeos beta-Amiloides/metabolismo
Colinesterases/metabolismo
[Mh] Termos MeSH secundário: Alcaloides/química
Alcaloides/metabolismo
Alcaloides/uso terapêutico
Doença de Alzheimer/tratamento farmacológico
Peptídeos beta-Amiloides/antagonistas & inibidores
Inibidores da Colinesterase/química
Inibidores da Colinesterase/metabolismo
Inibidores da Colinesterase/uso terapêutico
Colinesterases/química
Seres Humanos
Indanos/química
Indanos/metabolismo
Concentração Inibidora 50
Piperidinas/química
Piperidinas/metabolismo
Rivastigmina/química
Rivastigmina/metabolismo
Tacrina/química
Tacrina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Alkaloids); 0 (Amyloid beta-Peptides); 0 (Cholinesterase Inhibitors); 0 (Indans); 0 (Piperidines); 4VX7YNB537 (Tacrine); 8SSC91326P (donepezil); EC 3.1.1.8 (Cholinesterases); PKI06M3IW0 (Rivastigmine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171025
[Lr] Data última revisão:
171025
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170920
[St] Status:MEDLINE
[do] DOI:10.4155/fmc-2017-0094


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[PMID]:28810188
[Au] Autor:Reddy EK; Remya C; Mantosh K; Sajith AM; Omkumar RV; Sadasivan C; Anwar S
[Ad] Endereço:Division of Chemistry, Department of Science and Humanities, Vignan's Foundation for Science, Technology and Research University-VFSTRU (Vignan's University), Vadlamudi, Guntur 522 213, Andhra Pradesh, India.
[Ti] Título:Novel tacrine derivatives exhibiting improved acetylcholinesterase inhibition: Design, synthesis and biological evaluation.
[So] Source:Eur J Med Chem;139:367-377, 2017 Oct 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:A novel series of twenty four tacrine derivatives were designed and synthesised. Among these, thirteen were taken for the acetylcholinesterase (AChE) inhibition studies. Three compounds such as 4c, 6c and 6f were found to possess significant AChE inhibitory properties with IC values 12.97 ± 0.47 nM, 5.17 ± 0.24 nM and 7.14 ± 0.78 nM respectively. In silico docking studies revealed that these compounds can bind strongly in the active site of the enzyme and prevent enzyme-substrate interactions. On binding, the substituted groups were oriented either towards the peripheral anionic site (PAS) (Pocket A) or towards a hydrophobic cavity (pocket B) located near the active site. The cytotoxicity and hepatotoxicity of the compounds were tested using HEK-293 and HepG2 cell lines respectively. The compound 4c did not show any significant decrease in the cell viability even at a concentration of 300 µM indicating that its cytotoxicity and hepatotoxicity are significantly lesser compared to tacrine, due to the chemical modification. Based on the available results, it can be suggested that the compound 4c might be a potential drug lead compound with AChE inhibitory activity. However, further pharmacokinetic studies are necessary to comment on the efficacy of the compound as a drug for AD.
[Mh] Termos MeSH primário: Acetilcolinesterase/metabolismo
Inibidores da Colinesterase/farmacologia
Desenho de Drogas
Tacrina/farmacologia
[Mh] Termos MeSH secundário: Sobrevivência Celular/efeitos dos fármacos
Inibidores da Colinesterase/síntese química
Inibidores da Colinesterase/química
Relação Dose-Resposta a Droga
Células HEK293
Células Hep G2
Seres Humanos
Simulação de Acoplamento Molecular
Estrutura Molecular
Relação Estrutura-Atividade
Tacrina/síntese química
Tacrina/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cholinesterase Inhibitors); 4VX7YNB537 (Tacrine); EC 3.1.1.7 (Acetylcholinesterase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170816
[St] Status:MEDLINE


  6 / 1615 MEDLINE  
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[PMID]:28768927
[Au] Autor:Alshareef HF; Mohamed HAEH; Salaheldin AM
[Ad] Endereço:Chemistry Department, Faculty of Applied Science, Umm Alqura University.
[Ti] Título:Synthesis and Biological Evaluation of New Tacrine Analogues under Microwave Irradiation.
[So] Source:Chem Pharm Bull (Tokyo);65(8):732-738, 2017.
[Is] ISSN:1347-5223
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:Efficient routes to various kinds of heterocycles incorporating the p-halophenyl moiety have been synthesized. Different pyrrole derivatives have been synthesized, as well, by Thorpe-Ziegler cyclization. Therefore, we synthesized different analogues of tacrine by Friedländer reaction of o-amino nitriles (pyrazolo, furano and pyrrolo) with different cycloalkanones. The use of microwave irradiation leads to shorter production times and high product conversion. These synthesized compounds were biologically evaluated by Ellman's test on acetylcholinesterase inhibition.
[Mh] Termos MeSH primário: Acetilcolinesterase/metabolismo
Inibidores da Colinesterase/síntese química
Inibidores da Colinesterase/farmacologia
Micro-Ondas
Tacrina/análogos & derivados
Tacrina/farmacologia
[Mh] Termos MeSH secundário: Inibidores da Colinesterase/química
Seres Humanos
Estrutura Molecular
Neurônios Motores/enzimologia
Relação Estrutura-Atividade
Tacrina/síntese química
Tacrina/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cholinesterase Inhibitors); 4VX7YNB537 (Tacrine); EC 3.1.1.7 (Acetylcholinesterase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170829
[Lr] Data última revisão:
170829
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170804
[St] Status:MEDLINE
[do] DOI:10.1248/cpb.c17-00113


  7 / 1615 MEDLINE  
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[PMID]:28728108
[Au] Autor:Roldán-Peña JM; Alejandre-Ramos D; López Ó; Maya I; Lagunes I; Padrón JM; Peña-Altamira LE; Bartolini M; Monti B; Bolognesi ML; Fernández-Bolaños JG
[Ad] Endereço:Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, E-41071 Seville, Spain.
[Ti] Título:New tacrine dimers with antioxidant linkers as dual drugs: Anti-Alzheimer's and antiproliferative agents.
[So] Source:Eur J Med Chem;138:761-773, 2017 Sep 29.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:We have designed a series of tacrine-based homo- and heterodimers that incorporate an antioxidant tether (selenoureido, chalcogenide) as new dual compounds: for the treatment of Alzheimer's disease and as antiproliferative agents. Symmetrical homodimers bearing a dichalcogenide or selenide-based tether, the best compounds in the series, were found to be strong and highly selective electric eel AChE inhibitors, with inhibition constants within the low nanomolar range. This high inhibitory activity was confirmed on recombinant human AChE for the most interesting derivatives. The three most promising homodimers also showed a good inhibitory activity towards amyloid-ß self aggregation. The symmetric disulfide derivative bis[5-(1',2',3',4'-tetrahydroacridin-9'-ylamino)pentyl]disulfide (19) showed the best multipotent profile and was not neurotoxic on immortalized mouse cortical neurons even at 50 µM concentration. These results represent an improvement in activity and selectivity compared to parent tacrine, the first marketed drug against Alzheimer's disease. Title compounds also exhibited excellent in vitro antiproliferative activities against a panel of 6 human tumor cell lines, with GI values within the submicromolar range for the most potent derivatives (0.12-0.95 µM); such values represent a spectacular increase compared to currently-used chemotherapeutic agents, such as 5-FU (up to 306-fold) and cisplatin (up to 162-fold). Cell cycle experiments indicated the accumulation of cells in the G phase of the cycle, a different mechanism than the reported for cisplatin. The breast cancer cell lines turned out to be the most sensitive one of the panel tested.
[Mh] Termos MeSH primário: Doença de Alzheimer/tratamento farmacológico
Antineoplásicos/farmacologia
Antioxidantes/farmacologia
Calcogênios/farmacologia
Inibidores da Colinesterase/farmacologia
Compostos Organosselênicos/farmacologia
Tacrina/farmacologia
[Mh] Termos MeSH secundário: Acetilcolinesterase/metabolismo
Peptídeos beta-Amiloides/antagonistas & inibidores
Peptídeos beta-Amiloides/metabolismo
Animais
Antineoplásicos/síntese química
Antineoplásicos/química
Antioxidantes/química
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Calcogênios/química
Inibidores da Colinesterase/síntese química
Inibidores da Colinesterase/química
Dimerização
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Camundongos
Estrutura Molecular
Compostos Organosselênicos/química
Fragmentos de Peptídeos/antagonistas & inibidores
Fragmentos de Peptídeos/metabolismo
Agregados Proteicos/efeitos dos fármacos
Relação Estrutura-Atividade
Tacrina/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amyloid beta-Peptides); 0 (Antineoplastic Agents); 0 (Antioxidants); 0 (Chalcogens); 0 (Cholinesterase Inhibitors); 0 (Organoselenium Compounds); 0 (Peptide Fragments); 0 (Protein Aggregates); 0 (amyloid beta-protein (1-42)); 4VX7YNB537 (Tacrine); EC 3.1.1.7 (Acetylcholinesterase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170721
[St] Status:MEDLINE


  8 / 1615 MEDLINE  
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[PMID]:28714419
[Au] Autor:Lin H; Li Q; Gu K; Zhu J; Jiang X; Chen Y; Sun H
[Ad] Endereço:Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009. China.
[Ti] Título:Therapeutic Agents in Alzheimer's Disease Through a Multi-targetdirected Ligands Strategy: Recent Progress Based on Tacrine Core.
[So] Source:Curr Top Med Chem;17(27):3000-3016, 2017.
[Is] ISSN:1873-4294
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Alzheimer's Disease (AD) is one of the most common forms of dementia in elderly people. To date, efficacious therapeutic agent for the treatment of AD is still very limited, so it has long been a challenging and attractive task to discover new anti-AD drugs. Considering the multifactorial nature of AD, recently, the concept of Multi-Target-Directed Ligands (MTDLs) has emerged as a new strategy for designing therapeutic agents on AD. MTDLs are believed to exert their effects through simultaneously affecting multiple targets which contribute to etiology of AD. Therefore, MTDLs are considered to be more efficacious than mono-target agents. Tacrine is the first drug approved by Food and Drug Administration (FDA). Although the clinical use of tacrine is restricted because of its hepatotoxicity, the high Ligand Efficiency (LE) of this compound makes it an ideal component for designing MTDLs. This article provides an update review of the advances on the development of MTDLs based on tacrine. Case studies are carefully selected to show the detailed strategy on medicinal modification of Tacrine-Based MTDLs. Finally, several concerns and opinions on designing new MTDLs are discussed as well.
[Mh] Termos MeSH primário: Doença de Alzheimer/tratamento farmacológico
Fármacos Neuroprotetores/uso terapêutico
Tacrina/uso terapêutico
[Mh] Termos MeSH secundário: Doença de Alzheimer/metabolismo
Animais
Seres Humanos
Ligantes
Estrutura Molecular
Fármacos Neuroprotetores/química
Tacrina/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Ligands); 0 (Neuroprotective Agents); 4VX7YNB537 (Tacrine)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171110
[Lr] Data última revisão:
171110
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170718
[St] Status:MEDLINE
[do] DOI:10.2174/1568026617666170717114944


  9 / 1615 MEDLINE  
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[PMID]:28698054
[Au] Autor:Schmidt I; Göllner S; Fuß A; Stich A; Kucharski A; Schirmeister T; Katzowitsch E; Bruhn H; Miliu A; Krauth-Siegel RL; Holzgrabe U
[Ad] Endereço:Institute for Pharmacy and Food Chemistry, Julius-Maximilians-University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
[Ti] Título:Bistacrines as potential antitrypanosomal agents.
[So] Source:Bioorg Med Chem;25(16):4526-4531, 2017 Aug 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Human African Trypanosomiasis (HAT) is caused by two subspecies of the genus Trypanosoma, namely Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. The disease is fatal if left untreated and therapy is limited due to only five non-adequate drugs currently available. In preliminary studies, dimeric tacrine derivatives were found to inhibit parasite growth with IC -values in the nanomolar concentration range. This prompted the synthesis of a small, but smart library of monomeric and dimeric tacrine-type compounds and their evaluation of antiprotozoal activity. Rhodesain, a lysosomal cathepsin-L like cysteine protease of T. brucei rhodesiense is essential for parasite survival and likely target of the tacrine derivatives. In addition, the inhibition of trypanothione reductase by bistacrines was found. This flavoprotein oxidoreductase is the main defense against oxidative stress in the thiol redox system unique for protozoa.
[Mh] Termos MeSH primário: Tacrina/farmacologia
Tripanossomicidas/farmacologia
Trypanosoma brucei brucei/efeitos dos fármacos
Tripanossomíase Africana/tratamento farmacológico
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Camundongos
Estrutura Molecular
Testes de Sensibilidade Parasitária
Relação Estrutura-Atividade
Tacrina/química
Trypanosoma brucei brucei/citologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Trypanocidal Agents); 4VX7YNB537 (Tacrine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170814
[Lr] Data última revisão:
170814
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170713
[St] Status:MEDLINE


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[PMID]:28302511
[Au] Autor:Liu Z; Fang L; Zhang H; Gou S; Chen L
[Ad] Endereço:Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China; Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China.
[Ti] Título:Design, synthesis and biological evaluation of multifunctional tacrine-curcumin hybrids as new cholinesterase inhibitors with metal ions-chelating and neuroprotective property.
[So] Source:Bioorg Med Chem;25(8):2387-2398, 2017 Apr 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Total sixteen tacrine-curcumin hybrid compounds were designed and synthesized for the purpose of searching for multifunctional anti-Alzheimer agents. In vitro studies showed that these hybrid compounds showed good cholinesterase inhibitory activity. Particularly, the potency of K is even beyond tacrine. Some of the compounds exhibited different selectivity on acetylcholinesterase or butyrylcholinesterase due to the structural difference. Thus, the structure and activity relationship is summarized and further discussed based on molecular modeling studies. The ORAC and MTT assays indicated that the hybrid compounds possessed pronounced antioxidant activity and could effectively protect PC12 cells from the H O /Aß42-induced toxicity. Moreover, the hybrid compounds also showed positive metal ions-chelating ability in vitro, suggesting a potential to halt ion-induced Aß aggregation. All the obtained results demonstrated that the tacrine-curcumin hybrid compounds, in particular compound K , can be considered as potential therapeutic agents for Alzheimer's disease.
[Mh] Termos MeSH primário: Quelantes/farmacologia
Inibidores da Colinesterase/farmacologia
Curcumina/química
Fármacos Neuroprotetores/farmacologia
Tacrina/química
[Mh] Termos MeSH secundário: Animais
Quelantes/química
Inibidores da Colinesterase/química
Desenho de Drogas
Modelos Moleculares
Fármacos Neuroprotetores/química
Células PC12
Ratos
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Chelating Agents); 0 (Cholinesterase Inhibitors); 0 (Neuroprotective Agents); 4VX7YNB537 (Tacrine); IT942ZTH98 (Curcumin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170907
[Lr] Data última revisão:
170907
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170318
[St] Status:MEDLINE



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