- Novel tacrine-1,2,3-triazole hybrids: In vitro, in vivo biological evaluation and docking study of cholinesterase inhibitors
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A new series of tacrine-1,2,3-triazole hybrids were designed, synthesized, and evaluated as potent dual cholinesterase inhibitors. Most of synthesized compounds showed good in vitro inhibitory activities toward both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Among them, 7-chloro-N-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-1,2,3,4-tetrahydroacridin-9-amine (5l) was found to be the most potent anti-AChE derivative (IC50= 0.521 μM) and N-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-1,2,3,4-tetrahydroacridin-9-amine (5j) demonstrated the best anti-BChE activity (IC50= 0.055 μM). In vivo studies of compound 5l in Morris water maze task confirmed memory improvement in scopolamine-induced impairment. Also, molecular modeling and kinetic studies showed that compounds 5l and 5j bound simultaneously to the peripheral anionic site (PAS) and catalytic sites (CS) of the AChE and BChE.
- Najafi, Zahra,Mahdavi, Mohammad,Saeedi, Mina,Karimpour-Razkenari, Elahe,Asatouri, Raymond,Vafadarnejad, Fahimeh,Moghadam, Farshad Homayouni,Khanavi, Mahnaz,Sharifzadeh, Mohammad,Akbarzadeh, Tahmineh
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Read Online
- Novel tacrine-coumarin hybrids linked to 1,2,3-triazole as anti-Alzheimer's compounds: In vitro and in vivo biological evaluation and docking study
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A new series of tacrine-coumarin hybrids linked to 1,2,3-triazole were designed, synthesized, and tested as potent dual binding site cholinesterase inhibitors (ChEIs) for the treatment of Alzheimer's disease (AD). Among them, compound 8e was the most potent anti-AChE derivative (IC50 = 27 nM) and compound 8m displayed the best anti-BChE activity (IC50 = 6 nM) much more active than tacrine and donepezil as the reference drugs. Compound 8e was also evaluated for its BACE1 inhibitory activity and neuroprotectivity against PC12 cells exposed to Aβ25-35 which indicated low activity. Finally, in vivo studies by Morris water maze task showed that compound 8e significantly reversed scopolamine-induced memory deficit in rats.
- Najafi, Zahra,Mahdavi, Mohammad,Saeedi, Mina,Karimpour-Razkenari, Elahe,Edraki, Najmeh,Sharifzadeh, Mohammad,Khanavi, Mahnaz,Akbarzadeh, Tahmineh
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Read Online
- Synthesis and pharmacological evaluation of multifunctional tacrine derivatives against several disease pathways of AD
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A novel series of tacrine derivatives were designed and synthesized by combining caffeic acid (CA), ferulic acid (FA) and lipoic acid (LA) with tacrine. The antioxidant study revealed that all the hybrids have much more antioxidant capacities compared to
- Digiacomo, Maria,Chen, Ziwei,Wang, Shengnan,Lapucci, Annalina,Macchia, Marco,Yang, Xiaohong,Chu, Jiaqi,Han, Yifan,Pi, Rongbiao,Rapposelli, Simona
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Read Online
- Synthesis and evaluation of novel arylisoxazoles linked to tacrine moiety: in vitro and in vivo biological activities against Alzheimer’s disease
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Abstract: Alzheimer’s disease (AD) is now ranked as the third leading cause of death after heart disease and cancer. There is no definite cure for AD due to the multi-factorial nature of the disease, hence, multi-target-directed ligands (MTDLs) have attra
- Rastegari, Arezoo,Safavi, Maliheh,Vafadarnejad, Fahimeh,Najafi, Zahra,Hariri, Roshanak,Bukhari, Syed Nasir Abbas,Iraji, Aida,Edraki, Najmeh,Firuzi, Omidreza,Saeedi, Mina,Mahdavi, Mohammad,Akbarzadeh, Tahmineh
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p. 409 - 428
(2021/07/25)
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- Discovery of Novel Tacrine-Pyrimidone Hybrids as Potent Dual AChE/GSK-3 Inhibitors for the Treatment of Alzheimer's Disease
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Based on a multitarget strategy, a series of novel tacrine-pyrimidone hybrids were identified for the potential treatment of Alzheimer's disease (AD). Biological evaluation results demonstrated that these hybrids exhibited significant inhibitory activities toward acetylcholinesterase (AChE) and glycogen synthase kinase 3 (GSK-3). The optimal compound 27g possessed excellent dual AChE/GSK-3 inhibition both in terms of potency and equilibrium (AChE: IC50 = 51.1 nM; GSK-3β: IC50 = 89.3 nM) and displayed significant amelioration on cognitive deficits in scopolamine-induced amnesia mice and efficient reduction against phosphorylation of tau protein on Ser-199 and Ser-396 sites in glyceraldehyde (GA)-stimulated differentiated SH-SY5Y cells. Furthermore, compound 27g exhibited eligible pharmacokinetic properties, good kinase selectivity, and moderate neuroprotection against GA-induced reduction in cell viability and neurite damage in SH-SY5Y-derived neurons. The multifunctional profiles of compound 27g suggest that it deserves further investigation as a promising lead for the prospective treatment of AD.
- Yao, Hong,Uras, Giuseppe,Zhang, Pengfei,Xu, Shengtao,Yin, Ying,Liu, Jie,Qin, Shuai,Li, Xinuo,Allen, Stephanie,Bai, Renren,Gong, Qi,Zhang, Haiyan,Zhu, Zheying,Xu, Jinyi
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p. 7483 - 7506
(2021/06/28)
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- ACRIDIN-9-YL-AMINE, QUINOLIN-9-YL-AMINE, 1 -AMINO-9H-THIOXANTHENE-9-ONE AND BENZO[B][1,5]NAPHTHYRI DIN-10-YL-AMINE DERIVATIVES AS AUTOPHAGY INHIBITORS FOR TREATING CANCER
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This disclosure provides a cridin-9-yl-amine, quinolin-9-yl-amine, 1- amino-9H-thioxanthene-9-one and benzo[b][l,5]naphthyridin-10- yl-amine derivatives and structurally related compounds for use as autophagy inhibitors for treating cancer. The present description discloses the synthesis and characterisation of exemplary compounds as well as pharmacological data thereof (e.g. pages 77 to 155; examples 1 to 22; compound A; compounds 1 to 21; tables 1 to 3).
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Paragraph 0254; 0314
(2021/07/17)
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- NUCLEOSIDE AND NUCLEOTIDE CONJUGATE COMPOUNDS AND USES THEREOF
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This disclosure provides nucleoside and nucleotide conjugate compounds, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases,
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Paragraph 0196
(2021/10/11)
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- A tacrine-tetrahydroquinoline heterodimer potently inhibits acetylcholinesterase activity and enhances neurotransmission in mice
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Cholinergic neurons are ubiquitous and involved in various higher brain functions including learning and memory. Patients with Alzheimer's disease exhibit significant dysfunction and loss of cholinergic neurons. Meanwhile, such cholinergic deficits can be potentially relieved pharmacologically by increasing acetylcholine. Acetylcholinesterase (AChE) inhibitors have been used to improve cholinergic transmission in the brain for two decades and have proven effective for alleviating symptoms in the early stages of Alzheimer's disease. Therefore, the search for AChE inhibitors for drug development is ongoing. The enzymatic pocket of AChE has long been the target of several drug designs over the last two decades. The peripheral and catalytic sites of AChE are simultaneously bound by several dimeric molecules, enabling more-efficient inhibition. Here, we used 6-chlorotacrine and the tetrahydroquinolone moiety of huperzine A to design and synthesize a series of heterodimers that inhibit AChE at nanomolar potency. Specifically, compound 7b inhibits AChE with an IC50 1 nM and spares butyrylcholinesterase. Administration of 7b to mouse brain slices restores synaptic activity impaired by pirenzepine, a muscarinic M1-selective antagonist. Moreover, oral administration of 7b to C57BL/6 mice enhances hippocampal long-term potentiation in a dose-dependent manner and is detectable in the brain tissue. All these data supported that 7b is a potential cognitive enhancer and is worth for further exploration.
- Ip, Fanny C.F.,Fu, Guangmiao,Yang, Fengzhi,Kang, Fangyuan,Sun, Peiran,Ling, Choi Ying,Cheung, Kit,Xie, Fangzhou,Hu, Yueqing,Fu, Lei,Ip, Nancy Y.
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supporting information
(2021/09/18)
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- Multi-Targeting Tacrine Conjugates with Cholinesterase and Amyloid-Beta Inhibitory Activities: New Anti-Alzheimer's Agents
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Alzheimer's disease (AD) is a severe age dependent and chronic problem with no cure so far. The available treatments are temporary, acting over short period of time. The main pathological hallmark of the disease includes cholinergic dysfunction, oxidative stress, accumulation of Aβ fibrils and tau tangles. In context with the multi-factorial nature of this disease, two different series of molecules were developed to hit the multifactorial disease targets. Mainly, the molecules were designed to inhibit the AChE and aggregation of Aβ, and also oxidative damage. Two novel series of TAC-fenbufen/menbutone conjugated molecules were designed, synthesized and bio-assayed. All compounds showed inhibition capacity towards AChE, Aβ aggregation and moderate to good radical scavenging capacity. Particularly, five TAC-menbutone molecules showed improved AChE and Aβ aggregation inhibition capacity compared to TAC-fenbufen conjugated molecules. Overall, these novel series of molecules may be potential drug lead molecules in the treatment of AD.
- Hiremathad, Asha,Chaves, Sílvia,Keri, Rangappa S.
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- Novel tacrine–benzofuran hybrids as potential multi-target drug candidates for the treatment of Alzheimer’s Disease
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Pursuing the widespread interest on multi-target drugs to combat Alzheimer′s disease (AD), a new series of hybrids was designed and developed based on the repositioning of the well-known acetylcholinesterase (AChE) inhibitor, tacrine (TAC), by its coupling to benzofuran (BF) derivatives. The BF framework aims to endow the conjugate molecules with ability for inhibition of AChE (bimodal way) and of amyloid-beta peptide aggregation, besides providing metal (Fe, Cu) chelating ability and concomitant extra anti-oxidant activity, for the hybrids with hydroxyl substitution. The new TAC-BF conjugates showed very good activity for AChE inhibition (sub-micromolar range) and good capacity for the inhibition of self- and Cu-mediated Aβ aggregation, with dependence on the linker size and substituent groups of each main moiety. Neuroprotective effects were also found for the compounds through viability assays of neuroblastoma cells, after Aβ1-42 induced toxicity. Structure-activity relationship analysis provides insights on the best structural parameters, to take in consideration for future studies in view of potential applications in AD therapy.
- Cardoso, Sandra M.,Chand, Karam,Chaves, Sílvia,Fancellu, Gaia,Orlandini, Elisabetta,Piemontese, Luca,Santos, M. Amélia,Silva, Diana F.,Tomás, Daniel
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p. 211 - 226
(2019/11/29)
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- Functional characterization of multifunctional ligands targeting acetylcholinesterase and alpha 7 nicotinic acetylcholine receptor
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Alzheimer's disease (AD) is a neurodegenerative disorder associated with cholinergic dysfunction, provoking memory loss and cognitive dysfunction in elderly patients. The cholinergic hypothesis provided over the years with molecular targets for developing palliative treatments for AD, acting on the cholinergic system, namely, acetylcholinesterase and α7 nicotinic acetylcholine receptor (α7 nAChR). In our synthetic work, we used “click-chemistry” to synthesize two Multi Target Directed Ligands (MTDLs) MB105 and MB118 carrying tacrine and quinuclidine scaffolds which are known for their anticholinesterase and α7 nAChR agonist activities, respectively. Both, MB105 and MB118, inhibit human acetylcholinesterase and human butyrylcholinesterase in the nanomolar range. Electrophysiological recordings on Xenopus laevis oocytes expressing human α7 nAChR showed that MB105 and MB118 acted as partial agonists of the referred nicotinic receptor, albeit, with different potencies despite their similar structure. The different substitution at C-3 on the 2,3-disubstituted quinuclidine scaffold may account for the significantly lower potency of MB118 compared to MB105. Electrophysiological recordings also showed that the tacrine precursor MB320 behaved as a competitive antagonist of human α7 nAChR, in the micromolar range, while the quinuclidine synthetic precursor MB099 acted as a partial agonist. Taken all together, MB105 behaved as a partial agonist of α7 nAChR at concentrations where it completely inhibited human acetylcholinesterase activity paving the way for the design of novel MTDLs for palliative treatment of AD.
- Aráoz, Rómulo,Bartolini, Manuela,Cieslikiewicz-Bouet, Monika,Jean, Ludovic,Naldi, Marina,Pérez, Belén,Renard, Pierre-Yves,Servent, Denis
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- Multi-target tacrine derivative and preparation method and application thereof
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The invention provides a multi-target tacrine derivative and a preparation method and application thereof. The compound has the structure shown in a formula (I) (please see the specification in the formula (I)), wherein n is a natural number greater than 1; m is 1 or 2; p is 0 or 1; R1 is H or halogen; and Y is selected from the following structures (please see the specification for the structures) or, a pharmaceutically acceptable salt of a compound in a formula (X). According to the compound, activity of histone deacetylase (HDACs), acetylcholinesterase (AChE) or butyryl cholinesterase (BChE) can be effectively inhibited.
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Paragraph 0135-0137
(2019/12/25)
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- Dual functional cholinesterase and PDE4D inhibitors for the treatment of Alzheimer's disease: Design, synthesis and evaluation of tacrine-pyrazolo[3,4-b]pyridine hybrids
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A series of tacrine-pyrazolo[3,4-b]pyridine hybrids were synthesised and evaluated as dual cholinesterase (ChE) and phosphodiesterase 4D (PDE4D) inhibitors for the treatment of Alzheimer's disease (AD). Compound 10j, which is tacrine linked with pyrazolo[
- Pan, Tingting,Xie, Shishun,Zhou, Yan,Hu, Jinhui,Luo, Haibin,Li, Xingshu,Huang, Ling
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p. 2150 - 2152
(2019/07/08)
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- New multitarget hybrids bearing tacrine and phenylbenzothiazole motifs as potential drug candidates for Alzheimer’s disease
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Research on neurodegenerative brain disorders, namely the age-dependent Alzheimer’s disease (AD), has been intensified in the last decade due to the absence of a cure and the recognized increasing of life expectancy for populations. To address the multifa
- Rajeshwari, Rajeshwari,Chand, Karam,Candeias, Emanuel,Cardoso, Sandra M.,Chaves, Sílvia,Amélia Santos
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- Novel Tacrine-Hydroxyphenylbenzimidazole hybrids as potential multitarget drug candidates for Alzheimer's disease
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Alzheimer's disease (AD) is a severe age-dependent neurodegenerative disorder affecting millions of people, with no cure so far. The current treatments only achieve some temporary amelioration of the cognition symptoms. The main characteristics of the patient brains include the accumulation of amyloid plaques and neurofibrillary tangles (outside and inside the neurons) but also cholinergic deficit, increased oxidative stress and dyshomeostasis of transition metal ions. Considering the multi-factorial nature of AD, we report herein the development of a novel series of potential multi-target directed drugs which, besides the capacity to recover the cholinergic neurons, can also target other AD hallmarks. The novel series of tacrine-hydroxyphenylbenzimidazole (TAC-BIM) hybrid molecules has been designed, synthesized and studied for their multiple biological activities. These agents showed improved AChE inhibitory activity (IC50 in nanomolar range), as compared with the single drug tacrine (TAC), and also a high inhibition of self-induced- and Cu-induced-Aβ aggregation (up to 75%). They also present moderate radical scavenging activity and metal chelating ability. In addition, neuroprotective studies revealed that all these tested compounds are able to inhibit the neurotoxicity induced by Aβ and Fe/AscH(-) in neuronal cells. Hence, for this set of hybrids, structure-activity relationships are discussed and finally it is highlighted their real promising interest as potential anti-AD drugs.
- Hiremathad, Asha,Keri, Rangappa S.,Esteves, A. Raquel,Cardoso, Sandra M.,Chaves, Sílvia,Santos, M. Amélia
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p. 255 - 267
(2018/02/20)
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- Design, synthesis and biological evaluation of tacrine-1,2,3-triazole derivatives as potent cholinesterase inhibitors
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We report herein the design and synthesis of a series of 11 novel tacrine-1,2,3-triazole derivatives via a Cu(i)-catalyzed alkyne-azide 1,3-dipolar cycloaddition (CuAAC) reaction. The newly synthesized compounds were evaluated for their inhibition activity against Electrophorus electricus acetylcholinesterase (AChE) and horse serum butyrylcholinesterase (BChE) as potential drug targets for Alzheimer's disease (AD). Among the designed compounds, compound 8a2 exhibited potent inhibition against AChE and BChE with IC50 values of 4.89 μM and 3.61 μM, respectively. Further structure-activity relationship (SAR) and molecular modeling studies may provide valuable insights into the design of better tacrine-triazole analogues with potential therapeutic applications for AD.
- Wu, Gaochan,Gao, Yun,Kang, Dongwei,Huang, Boshi,Huo, Zhipeng,Liu, Huiqing,Poongavanam, Vasanthanathan,Zhan, Peng,Liu, Xinyong
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p. 149 - 159
(2018/02/07)
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- Novel tacrine-scutellarin hybrids as multipotent anti-Alzheimer’s agents: Design, synthesis and biological evaluation
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A novel series of 6-chlorotacrine-scutellarin hybrids was designed, synthesized and the biological activity as potential anti-Alzheimer’s agents was assessed. Their inhibitory activity towards human acetylcholinesterase (hAChE) and human butyrylcholineste
- Spilovska, Katarina,Korabecny, Jan,Sepsova, Vendula,Jun, Daniel,Hrabinova, Martina,Jost, Petr,Muckova, Lubica,Soukup, Ondrej,Janockova, Jana,Kucera, Tomas,Dolezal, Rafael,Mezeiova, Eva,Kaping, Daniel,Kuca, Kamil
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- Structure–activity relationship studies of benzyl-, phenethyl-, and pyridyl-substituted tetrahydroacridin-9-amines as multitargeting agents to treat Alzheimer's disease
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A library of substituted tetrahydroacridin-9-amine derivatives were designed, synthesized, and evaluated as dual cholinesterase and amyloid aggregation inhibitors. Compound 8e (N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine) was identified as a potent inhibitor of butyrylcholinesterase (BuChE IC50?=?20?nm; AChE IC50?=?2.2?μm) and was able to inhibit amyloid aggregation (40% inhibition at 25?μm). Compounds 9e (6-chloro-N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine, AChE IC50?=?0.8?μm; BuChE IC50?=?1.4?μm; Aβ-aggregation inhibition?=?75.7% inhibition at 25?μm) and 11b (6-chloro-N-(3,4-dimethoxyphenethyl)-1,2,3,4-tetrahydroacridin-9-amine, AChE IC50?=?0.6?μm; BuChE IC50?=?1.9?μm; Aβ-aggregation inhibition?=?85.9% inhibition at 25?μm) were identified as the best compounds with dual cholinesterase and amyloid aggregation inhibition. The picolylamine-substituted compound 12c (6-chloro-N-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydroacridin-9-amine) was the most potent AChE inhibitor (IC50?=?90?nm). These investigations demonstrate the utility of 3,4-dimethoxyphenyl substituent as a novel pharmacophore possessing dual cholinesterase inhibition and anti-Aβ-aggregation properties that can be used in the design and development of small molecules with multitargeting ability to treat Alzheimer's disease.
- Osman, Wesseem,Mohamed, Tarek,Sit, Victor Munsing,Vasefi, Maryam S.,Beazely, Michael A.,Rao, Praveen P. N.
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p. 710 - 723
(2016/10/25)
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- Compound and its as L-type calcium channel blocker or/and application of acetylcholine esterase inhibitors
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Disclosed in this invention are compounds and the uses as L-type calcium channel blocker and/or acetylcholinesterase inhibitor thereof. The uses of said compounds in the manufactures of a medicament for the treatment of cardiovascular diseases, apoplexy or senile dementia are also disclosed in the present invention.
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Paragraph 0202; 0204-0205
(2016/10/07)
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- Hydrogenated acridine derivative and its application
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The invention relates to the field of chemical synthesis, and particularly relates to a compound with the general formula being Y-L-X and an application of the compound serving as a calcium channel blocking agent or/and an acetylcholinesterase inhibitor. The compound with the general formula being Y-L-X can be used for adjusting calcium homeostasis and treating cardiovascular diseases, stroke or dementia.
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Paragraph 0050; 0051; 0052; 0053
(2016/10/08)
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- Tacrine-allyl/propargylcysteine-benzothiazole trihybrids as potential anti-Alzheimer's drug candidates
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On continuing our research into new drug candidates for Alzheimer's disease (AD), we have designed, synthesized and evaluated a series of multifunctional trihybrid agents. The design strategy was based on the incorporation of a benzothiazole (BTA) moiety on a series of very recently reported bihybrids, resulting from the conjugation of a tacrine (TAC) with natural based moieties, namely S-allylcysteine (SAC) (garlic constituent) and S-propargylcysteine (SPRC). Thus, in addition to the acetylcholinesterase inhibition (AChEI) and anti-ROS capacity of the bihybrids (TAC-SAC/SPRC), the new trihybrids (TAC-SAC/SPRC-BTA) appeared endowed with a 5-fold capacity for inhibition of amyloid beta-peptide (Aβ) aggregation. The BTA moiety led also to considerable enhancement of the AChEI on the trihybrids, which molecular modeling suggested as being due to simultaneous binding to the catalytic active site and peripheral anionic site of AChE. The trihybrids were also assessed for MAO inhibition, but resulted in lower activity than expected, ascribed to the low accessibility of the propargyl groups to the enzyme active site. Finally, the effects of the compounds on the viability of neuroblastome cells stressed with Aβ42 and H2O2 showed moderate cell protection. Overall, the performed studies illustrate the importance (and limitations) of enclosing several molecular scaffolds in one molecular entity to allow the modulation of multiple AD targets.
- Hiremathad, Asha,Chand, Karam,Esteves, A. Raquel,Cardoso, Sandra M.,Ramsay, Rona R.,Chaves, Sílvia,Keri, Rangappa S.,Santos, M. Amélia
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p. 53519 - 53532
(2016/06/14)
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- Design and synthesis of novel anti-Alzheimer's agents: Acridine-chromenone and quinoline-chromenone hybrids
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A novel series of acridine-chromenone and quinoline-chromenone hybrids were designed, synthesized, and evaluated as anti-Alzheimer's agents. All synthesized compounds were evaluated as cholinesterases (ChEs) inhibitors and among them, 7-(4-(6-chloro-2,3-d
- Najafi, Zahra,Saeedi, Mina,Mahdavi, Mohammad,Sabourian, Reyhaneh,Khanavi, Mahnaz,Tehrani, Maliheh Barazandeh,Moghadam, Farshad Homayouni,Edraki, Najmeh,Karimpor-Razkenari, Elahe,Sharifzadeh, Mohammad,Foroumadi, Alireza,Shafiee, Abbas,Akbarzadeh, Tahmineh
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- Bistacrine derivatives as new potent antimalarials
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Linking two tacrine molecules results in a tremendous increase of activity against Plasmodia in comparison to the monomer. This finding prompted the synthesis of a library of monomeric and dimeric tacrine derivatives in order to derive structure–activity relationships. The most active compounds towards chloroquine sensitive Plasmodium strain 3D7 and chloroquine resistant strain Dd2 show IC50values in the nanomolar range of concentration, low cytotoxicity and target the cysteine protease falcipain-2, which is essential for parasite growth.
- Schmidt, Ines,Pradel, Gabriele,Sologub, Ludmilla,Golzmann, Alexandra,Ngwa, Che J.,Kucharski, Anna,Schirmeister, Tanja,Holzgrabe, Ulrike
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p. 3636 - 3642
(2016/07/20)
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- New Tacrine Hybrids with Natural-Based Cysteine Derivatives as Multitargeted Drugs for Potential Treatment of Alzheimer's Disease
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Alzheimer's disease (AD) is a devastating age-dependent neurodegenerative disorder. The main hallmarks are impairment of cholinergic system and accumulation in brain of beta-amyloid (Aβ) aggregates, which have been associated with oxidative damage and dyshomeostasis of redox-active biometals. The absence of an efficient treatment that could delay or cure AD has been attributed to the complexity and multifactorial nature of this disease. With this in mind and the recent interest on natural-based drugs, we have explored a set of natural-based hybrid compounds by conjugation of a tacrine moiety with an S-allylcysteine (garlic constituent) or S-propargylcysteine moiety aimed at improving the cholinergic system and neuroprotective capacity. The docking modeling studies allowed the selection of linkers to optimize the bimodal drug interaction with acetylcholinesterase enzyme (AChE) active site. The compounds were evaluated for some representative biological properties, including AChE activity and Aβ aggregation inhibition, as well as for their neuroprotective activity to Aβ- and ROS-induced cellular toxicity.
- Keri, Rangappa S.,Quintanova, Catarina,Chaves, Sílvia,Silva, Diana F.,Cardoso, Sandra M.,Santos, M. Amélia
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p. 101 - 111
(2016/02/03)
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- Design, synthesis and evaluation of novel tacrine-rhein hybrids as multifunctional agents for the treatment of Alzheimer's disease
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A series of tacrine-rhein hybrid compounds have been designed and synthesized as novel multifunctional potent ChE inhibitors. Most of the compounds inhibited ChEs in the nanomolar range in vitro effectively. Compound 10b was one of the most potent inhibitors and was 5-fold more active than tacrine toward AChE, and it also showed a moderate BuChE inhibition with an IC50 value of 200 nM. Kinetic and molecular modeling studies of 10b also indicated that it was a mixed-type inhibitor binding simultaneously to the active and peripheral sites of AChE. In inhibition of the AChE-induced Aβ aggregation assay, compound 10b (70.2% at 100 μM) showed the greatest inhibitory activity. In addition, 10b showed metal-chelating property and low hepatotoxicity. These results suggested that 10b might be an excellent multifunctional agent for AD treatment.
- Li, Su-Yi,Jiang, Neng,Xie, Sai-Sai,Wang, Kelvin D. G.,Wang, Xiao-Bing,Kong, Ling-Yi
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p. 801 - 814
(2014/01/23)
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- Design, synthesis and pharmacological evaluation of novel tacrine-caffeic acid hybrids as multi-targeted compounds against Alzheimer's disease
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A novel series of tacrine-caffeic acid hybrids (5a-f) were designed and synthesized by combining caffeic acid (CA) with tacrine. The antioxidant study revealed that all the hybrids have much more antioxidant capacities compared to CA. Among these compound
- Chao, Xiaojuan,He, Xixin,Yang, Yilin,Zhou, Xie,Jin, Minghua,Liu, Shu,Cheng, Zhiyi,Liu, Peiqing,Wang, Yuting,Yu, Jianchen,Tan, Yi,Huang, Yingjuan,Qin, Jian,Rapposelli, Simona,Pi, Rongbiao
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p. 6498 - 6502
(2012/11/07)
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- O-Hydroxyl- or o-amino benzylamine-tacrine hybrids: Multifunctional biometals chelators, antioxidants, and inhibitors of cholinesterase activity and amyloid-β aggregation
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In an effort to identify novel multifunctional drug candidates for the treatment of Alzheimer's disease (AD), a series of hybrid molecules were synthesised by reacting N-(aminoalkyl)tacrine with salicylic aldehyde or derivatives of 2-aminobenzaldehyde. Th
- Mao, Fei,Huang, Ling,Luo, Zonghua,Liu, Anqiu,Lu, Chuanjun,Xie, Zhiyong,Li, Xingshu
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p. 5884 - 5892
(2012/11/06)
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- Anti-prion activities and drug-like potential of functionalized quinacrine analogs with basic phenyl residues at the 9-amino position
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In this paper, we report the synthesis and cell-based anti-prion activity of quinacrine analogs derived by replacing the basic alkyl side chain of quinacrine with 4-(4-methylpiperazin-I-yl)phenyl, (1-benzylpiperidin-4-yl) and their structural variants. Several promising analogs were found that have a more favorable anti-prion profile than quinacrine in terms of potency and activity across different prion-infected murine cell models. They also exhibited greater binding affinities for a human prion protein fragment (hPrP121-231) than quinacrine, and had permeabilities on the PAMPA-BBB assay that fall within the range of CNS permeant candidates. When evaluated on bidirectional assays on a Pgp overexpressing cell line, one analog was less susceptible to Pgp efflux activity compared to quinacrine. Taken together, the results point to an important role for the substituted 9-amino side chain attached to the acridine, tetrahydroacridine and quinoline scaffolds. The nature of this side chain influenced cell-based potency, PAMPA permeability and binding affinity to hPrP121-231.
- Nguyen, Thuy,Sakasegawa, Yuji,Doh-Ura, Katsumi,Go, Mei-Lin
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experimental part
p. 2917 - 2929
(2011/07/08)
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- Palladium-catalyzed preparation of N-alkylated tacrine and huprine compounds
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An efficient preparation of N-alkylated tacrine and huprine compounds using palladium-catalyzed amination was developed. Cross-coupling reactions with chloroquinolines and primary amines were achieved in good to excellent yields (50-95%) following microwa
- Ronco, Cyril,Jean, Ludovic,Outaabout, Hakim,Renard, Pierre-Yves
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supporting information; experimental part
p. 302 - 310
(2011/02/28)
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- Heterodimers and Methods of Using Them
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Novel heterodimers of tetrahydroacridines and tetrahydroquinolinones are disclosed. The heterodimers are capable of acting as both acetylcholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists. The heterodimers may be used to improve cognitive defects via treatment or prevention in both humans and non-humans.
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Page/Page column 10
(2008/12/07)
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- Homodimeric tacrine congeners as acetylcholinesterase inhibitors
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In the search for highly selective and potent derivatives of tacrine (1a), a number of homodimeric tacrine congeners were synthesized and conducted for their effects on rat acetylcholinesterase (ACHE) and human butyrylcholinesterase (BChE) inhibitions. Heptylene-linked bis-(6-chloro)-tacrine (3h) was found up to 3000- and 3-fold more potent in inhibiting rat AChE than tacrine and the unsubstituted bis-tacrine 3b, respectively. Changes in the size of the carbocyclic ring of the dimeric tacrine reduced both the selectivity and the potency of AChE inhibition as compared to 3b. Inserting an aza into the tacrine nucleus as the desired isosteres 3j-m resulted in moderate potency but tended to be detrimental to selectivity. The pronounced enhancement of AChE inhibition potency and AChE/BChE selectivity was achieved with incorporation of a halogen at the 6-position of homodimeric tacrines. The assay results of 3a-m also provided evidence that the 7-methylene tether tended to be optimal to AChE inhibition potency.
- Hu, Ming-Kuan,Wu, Li-Ju,Hsiao, George,Yen, Mao-Hsiung
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p. 2277 - 2282
(2007/10/03)
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- Tacrine derivatives for treating Alzheimer's disease
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A series of tacrine derivatives has be synthesized and disclosed. These tacrine derivatives were claimed to be new and be useful for the treatment of Alzheimer's disease alone or in combination with other drugs for Alzheimer's disease. These tacrine derivatives may be formulated into suitable pharmaceutical dosage forms for the treatment of Alzheimer's disease.
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- A facile synthesis of bis-tacrine isosteres
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An efficient synthesis of highly potent and selective acetylcholinesterase (AChE) inhibitors, bis-tacrines and their isosteres 2-4, has been accomplished by bis-amination of 9-chloro-tetrahydroacridine (9a) and its analogs. The critical intermediates were concisely prepared in situ by heating the corresponding ortho-amino aromatic acids and cycloketones in the presence of phosphorus oxychloride. (C) 2000 Elsevier Science Ltd.
- Hu, Ming-Kuan,Lu, Chih-Feng
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p. 1815 - 1818
(2007/10/03)
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- SAR of 9-amino-1,2,3-4-tetrahydroacridine-based acetylcholinesterase inhibitors: Synthesis, enzyme inhibitory activity, QSAR, and structure-based CoMFA of tacrine analogues
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In this study, we attempted to derive a comprehensive SAR picture for the class of acetylcholinesterase (ACHE) inhibitors related to tacrine, a drug currently in use for the treatment of the Alzheimer's disease. To this aim, we synthesized and tested a series of 9-amino-1,2,3,4-tetrahydroacridine derivatives substituted in the positions 6 and 7 of the acridine nucleus and bearing selected groups on the 9-amino function. By means of the Hansch approach, QSAR equations were obtained, quantitatively accounting for both the detrimental steric effect of substituents in position 7 and the favorable electron-attracting effect exerted by substituents in positions 6 and 7 of the 9-amino-1,2,3,4-tetrahydroacridine derivatives. The three-dimensional (3D) properties of the inhibitors were taken into consideration by performing a CoMFA analysis on the series of AChE inhibitors made by 12 9-amino-1,2,3,4- tetrahydroacridines and 13 11H-indeno[1,2-b]quinolin-10-ylamines previously developed in our laboratory. The alignment of the molecules to be submitted to the CoMFA procedure was carried out by taking advantage of docking models calculated for the interactions of both the unsubstituted 9-amino-1,2,3,4- tetrahydroacridine and 11H-indeno[1,2-b]quinolin-10-ylamine with the target enzyme. A highly significant CoMFA model was obtained using the steric field alone, and the features of such a 3D QSAR model were compared with the classical QSAR equations previously calculated. The two models appeared consistent, the main aspects they had in common being (a) the individuation of the strongly negative contribution of the substituents in position 7 of tacrine and (b) a tentative assignment of the hydrophobic character to the favorable effect exerted by the substituents in position 6. Finally, a new previously unreported tacrine derivative designed on the basis of both the classical and the 3D QSAR equations was synthesized and kinetically evaluated, to test the predictive ability of the QSAR models. The 6-bromo-9- amino-1,2,3,4-tetrahydroacridine was predicted to have a pIC50 value of 7.31 by the classical QSAR model and 7.40 by the CoMFA model, while its experimental IC50 value was equal to 0.066 (±0.009) μM, corresponding to a pIC50 of 7.18, showing a reasonable agreement between predicted and observed AChE inhibition data.
- Recanatini, Maurizio,Cavalli, Andrea,Belluti, Federica,Piazzi, Lorna,Rampa, Angela,Bisi, Alessandra,Gobbi, Silvia,Valenti, Piero,Andrisano, Vincenza,Bartolini, Manuela,Cavrini, Vanni
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p. 2007 - 2018
(2007/10/03)
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