5778-71-2Relevant academic research and scientific papers
Trapping of the highly strained [5](2,4)quinolinophane system
van Eis, Maurice J.,Lutz, Martin,Spek, Anthony L.,de Wolf, Willem H.,Bickelhaupt, Friedrich
, p. 1689 - 1694 (2007)
The highly strained [5](2,4)quinolinophane system can be generated as an intermediate (2b), which is extremely susceptible towards the attack of both nucleophilic and electrophilic species. Addition of water at the carbon bridgehead C2 occurs rapidly and is followed by rearrangements to give a strain free product 10. An unusual carbene addition at the N1{double bond, long}C2 bond of 2b is proposed to explain the formation of the strained 'anti-Bredt' type olefin 11.
Novel Tacrine-Benzofuran Hybrids as Potent Multitarget-Directed Ligands for the Treatment of Alzheimers Disease: Design, Synthesis, Biological Evaluation, and X-ray Crystallography
Zha, Xiaoming,Lamba, Doriano,Zhang, Lili,Lou, Yinghan,Xu, Changxu,Kang, Di,Chen, Li,Xu, Yungen,Zhang, Luyong,De Simone, Angela,Samez, Sarah,Pesaresi, Alessandro,Stojan, Jure,Lopez, Manuela G.,Egea, Javier,Andrisano, Vincenza,Bartolini, Manuela
, p. 114 - 131 (2016)
Twenty-six new tacrine-benzofuran hybrids were designed, synthesized, and evaluated in vitro on key molecular targets for Alzheimers disease. Most hybrids exhibited good inhibitory activities on cholinesterases and β-amyloid self-aggregation. Selected compounds displayed significant inhibition of human β-secretase-1 (hBACE-1). Among the 26 hybrids, 2e showed the most interesting profile as a subnanomolar selective inhibitor of human acetylcholinesterase (hAChE) (IC50 = 0.86 nM) and a good inhibitor of both β-amyloid aggregation (hAChE- and self-induced, 61.3% and 58.4%, respectively) and hBACE-1 activity (IC50 = 1.35 μM). Kinetic studies showed that 2e acted as a slow, tight-binding, mixed-type inhibitor, while X-ray crystallographic studies highlighted the ability of 2e to induce large-scale structural changes in the active-site gorge of Torpedo californica AChE (TcAChE), with significant implications for structure-based drug design. In vivo studies confirmed that 2e significantly ameliorates performances of scopolamine-treated ICR mice. Finally, 2e administration did not exhibit significant hepatotoxicity.
New Hybrids of 4-Amino-2,3-polymethylene-quinoline and p-Tolylsulfonamide as Dual Inhibitors of Acetyl- And Butyrylcholinesterase and Potential Multifunctional Agents for Alzheimer’s Disease Treatment
Astakhova, Tatiana Yu.,Bachurin, Sergey O.,Boltneva, Natalia P.,Kovaleva, Nadezhda V.,Lushchekina, Sofya V.,Makhaeva, Galina F.,Palyulin, Vladimir A.,Proshin, Alexey N.,Radchenko, Eugene V.,Richardson, Rudy J.,Rudakova, Elena V.,Serkov, Igor V.
, (2020/09/17)
New hybrid compounds of 4-amino-2,3-polymethylene-quinoline containing different sizes of the aliphatic ring and linked to p-tolylsulfonamide with alkylene spacers of increasing length were synthesized as potential drugs for treatment of Alzheimer’s disease (AD). All compounds were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. The lead compound 4-methyl-N-(5-(1,2,3,4-tetrahydro-acridin-9-ylamino)-pentyl)-benzenesulfonamide (7h) exhibited an IC50 (AChE) = 0.131 ± 0.01 μM (five times more potent than tacrine), IC50(BChE) = 0.0680 ± 0.0014 μM, and 17.5 ± 1.5% propidium displacement at 20 μM. The compounds possessed low activity against carboxylesterase, indicating a likely absence of unwanted drug-drug interactions in clinical use. Kinetics studies were consistent with mixed-type reversible inhibition of both cholinesterases. Molecular docking demonstrated dual binding sites of the conjugates in AChE and clarified the differences in the structure-activity relationships for AChE and BChE inhibition. The conjugates could bind to the AChE peripheral anionic site and displace propidium, indicating their potential to block AChE-induced β-amyloid aggregation, thereby exerting a disease-modifying effect. All compounds demonstrated low antioxidant activity. Computational ADMET profiles predicted that all compounds would have good intestinal absorption, medium blood-brain barrier permeability, and medium cardiac toxicity risk. Overall, the results indicate that the novel conjugates show promise for further development and optimization as multitarget anti-AD agents.
A simple structural modification to thiazole orange to improve the selective detection of G-quadruplexes
Guo, Rui-Jun,Yan, Jin-Wu,Chen, Shuo-Bin,Gu, Lian-Quan,Huang, Zhi-Shu,Tan, Jia-Heng
, p. 76 - 85 (2015/12/18)
Thiazole orange is a commonly used cyanine dye for binding to nucleic acids. Recently, it has been used for the detection of G-quadruplexes. However, thiazole orange is non-selective for G-quadruplex and other nucleic acids, thus hampering its further app
Design and synthesis of novel anti-Alzheimer's agents: Acridine-chromenone and quinoline-chromenone hybrids
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
, p. 84 - 94 (2016/07/06)
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
Design, synthesis and evaluation of novel tacrine-rhein hybrids as multifunctional agents for the treatment of Alzheimer's disease
Li, Su-Yi,Jiang, Neng,Xie, Sai-Sai,Wang, Kelvin D. G.,Wang, Xiao-Bing,Kong, Ling-Yi
, p. 801 - 814 (2014/01/23)
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.
Synthesis, kinetic studies and molecular modeling of novel tacrine dimers as cholinesterase inhibitors
De Aquino, Roney Anderson Nascimento,Modolo, Luzia Valentina,Alves, Rosemeire Brondi,De Fatima, Angelo
, p. 8395 - 8409 (2013/12/04)
This study presents the synthesis of 15 new tacrine dimers as well as the Ki and IC50 results, studies of the kinetic mechanism, and molecular docking analysis of the dimers in relation to the cholinesterases hAChE, hBChE, EeAChE and eqBChE. In addition to spectroscopic characterization, X-ray structure determination was performed for two of the new compounds. These new dimers were found to be mixed nanomolar inhibitors of the evaluated targets with a broad and significant selectivity profile, and these properties are dependent on both the type of the linker and the volume of the hydroacridine alicyclic ring. The results indicate that the aromatic linkers play a significant role in generating specific interactions with the half-gorge region of the catalytic center. Thus, these types of linkers can positively modulate the electronic properties of the tacrine dimers studied with an improvement of their cholinesterase inhibition activity.
Hybrids of oxoisoaporphine-tacrine congeners: Novel acetylcholinesterase and acetylcholinesterase-induced β-amyloid aggregation inhibitors
Tang, Huang,Zhao, Li-Zhen,Zhao, Hao-Tao,Huang, Shi-Liang,Zhong, Shu-Ming,Qin, Jiang-Ke,Chen, Zhen-Feng,Huang, Zhi-Shu,Liang, Hong
experimental part, p. 4970 - 4979 (2011/11/29)
A series of dual binding site acetylcholinesterase (AChE) inhibitors have been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), AChE-induced and self-induced β-amyloid (Aβ) aggregation. The new hybrids consist of a unit of 1-azabenzanthrone and a tacrine or its congener, connected through an oligomethylene linker containing an amine group at variable position. These hybrids exhibit high AChE inhibitory activity with IC50 values in the nanomolar range in most cases. Moreover, five out of the 12 hybrids of this series, particularly those bearing a tetrahydroacridine moiety, exhibit a significant in vitro inhibitory activity toward the AChE-induced and self-induced Aβ aggregation, which makes them promising anti-Alzheimer drug candidates.
A new class of histamine H3-receptor antagonists: Synthesis and structure - Activity relationships of 7,8,9,10-Tetrahydro-6H-cyclohepta[b]quinolines
Turner, Sean C.,Esbenshade, Timothy A.,Bennani, Youssef L.,Hancock, Arthur A.
, p. 2131 - 2135 (2007/10/03)
The synthesis and biological evaluation of novel cycloheptaquinoline antagonists of the human H3 receptor are described. Two series of compounds, bearing either an amino substituent or an alkyne linker at the 11-position, were investigated. Modifications of the amino substituents, optimization of chain length and the effect of conformational restraints are described. Several compounds with high affinity and selectivity for the H3 receptor were discovered.
Homodimeric tacrine congeners as acetylcholinesterase inhibitors
Hu, Ming-Kuan,Wu, Li-Ju,Hsiao, George,Yen, Mao-Hsiung
, p. 2277 - 2282 (2007/10/03)
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.
