- Hybrids of oxoisoaporphine-tacrine congeners: Novel acetylcholinesterase and acetylcholinesterase-induced β-amyloid aggregation inhibitors
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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.
- 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
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- 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
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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.
- 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.
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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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- 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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- A simple structural modification to thiazole orange to improve the selective detection of G-quadruplexes
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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
- Guo, Rui-Jun,Yan, Jin-Wu,Chen, Shuo-Bin,Gu, Lian-Quan,Huang, Zhi-Shu,Tan, Jia-Heng
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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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- Synthesis, kinetic studies and molecular modeling of novel tacrine dimers as cholinesterase inhibitors
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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.
- De Aquino, Roney Anderson Nascimento,Modolo, Luzia Valentina,Alves, Rosemeire Brondi,De Fatima, Angelo
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- Design, Synthesis, and Evaluation of New Quinazolinone Derivatives that Inhibit Bloom Syndrome Protein (BLM) Helicase, Trigger DNA Damage at the Telomere Region, and Synergize with PARP Inhibitors
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DNA damage response (DDR) pathways are crucial for the survival of cancer cells and are attractive targets for cancer therapy. Bloom syndrome protein (BLM) is a DNA helicase that performs important roles in DDR pathways. Our previous study discovered an effective new BLM inhibitor with a quinazolinone scaffold by a screening assay. Herein, to better understand the structure-activity relationship (SAR) and biological roles of the BLM inhibitor, a series of new derivatives were designed, synthesized, and evaluated based on this scaffold. Among them, compound 9h exhibited nanomolar inhibitory activity and binding affinity for BLM. 9h could effectively disrupt BLM recruitment to DNA in cells. Furthermore, 9h inhibited the proliferation of the colorectal cell line HCT116 by significantly triggering DNA damage in the telomere region and inducing apoptosis, especially in combination with a poly (ADP-ribose) polymerase (PARP) inhibitor. This result suggested a synthetic lethal effect between the BLM and PARP inhibitors in DDR pathways.
- Wang, Chen-Xi,Zhang, Zi-Lin,Yin, Qi-Kun,Tu, Jia-Li,Wang, Jia-En,Xu, Yao-Hao,Rao, Yong,Ou, Tian-Miao,Huang, Shi-Liang,Li, Ding,Wang, Hong-Gen,Li, Qing-Jiang,Tan, Jia-Heng,Chen, Shuo-Bin,Huang, Zhi-Shu
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p. 9752 - 9772
(2020/10/19)
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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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- Synthesis and biological activity of new 2,3-dihydro-1H-cyclopenta[b]- quinoline derivatives as acetylcholinesterase inhibitors
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In this study we present synthesis and biological evaluation of derivatives of 4-fluorobenzoic acid and 2,3-dihydro-1H-cyclopenta[b]quinoline towards inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Synthesis of acquired molecul
- Szymanski, Pawel,Markowicz, Magdalena,Bajda, Marek,Malawska, Barbara,Mikiciuk-Olasik, Elzbieta
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experimental part
p. 645 - 654
(2012/09/22)
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- Development of a universal colorimetric indicator for G-quadruplex structures by the fusion of thiazole orange and isaindigotone skeleton
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The rapid and convenient method for identification of all kinds of G-quadruplex is highly desirable. In the present study, a novel colorimetric indicator for a vast variety of G-quadruplex was designed and synthesized on the basis of thiazole orange and isaindigotone skeleton. Its distinct color change enables label-free visual detection of G-quadruplexes, which is due to the disassembly of dye H-aggregates to monomers. This specific detection of G-quadruplex arises from its end-stacking interaction with G-quartet. On the basis of this universal indicator, a facile approach for large-scale identification of G-quadruplex was developed.
- Yan, Jin-Wu,Ye, Wen-Jie,Chen, Shuo-Bin,Wu, Wei-Bin,Hou, Jin-Qiang,Ou, Tian-Miao,Tan, Jia-Heng,Li, Ding,Gu, Lian-Quan,Huang, Zhi-Shu
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scheme or table
p. 6288 - 6292
(2012/10/08)
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- SUBSTITUTED N-ARYL-1H-PYRAZOLO[3,4-b]QUINOLIN-4-AMINES AND ANALOGS AS ACTIVATORS OF CASPASES AND INDUCERS OF APOPTOSIS
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The present invention is directed to substituted N-aryl-1H-pyrazolo[3,4-b]quinolin-4-amines and analogs thereof, represented by the general Formula (I): wherein Q, Y, Z, R4-R7, X and Ar are defined herein. The present invention also
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Page/Page column 39
(2008/06/13)
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- Polycyclic compounds
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PCT No. PCT/GB96/02945 Sec. 371 Date Aug. 25, 1998 Sec. 102(e) Date Aug. 25, 1998 PCT Filed Nov. 28, 1996 PCT Pub. No. WO97/19929 PCT Pub. Date Jun. 5, 1997Compounds of Formula (I), methods for their preparation, pharmaceutical formulations and use thereof.
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