Novel Indole-Isoxazole Hybrids: Synthesis and In Vitro Anti-Cholinesterase Activity

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In this work, a novel series of arylisoxazole-phenylpiperazines were designed, synthesized, and evaluated toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Our results revealed that [5-(2chlorophenyl)-1,2-oxazol-3-yl](4-phenylpiperazin-1-yl)methanone (5c) was the most potent AChE inhibitor with IC 50 of 21.85 μM. It should be noted that most of synthesized compounds showed no BChE inhibitory activity and [5-(2-fluorophenyl)-1,2-oxazol-3-yl](4-phenylpiperazin-1-yl)methanone (5a) was the most active anti-BChE derivative (IC 50 = 51.66 μM). Also, kinetic studies for the AChE and BChE inhibitory activity of compounds 5c and 5a confirmed that they have simultaneously bound to the catalytic site (CS) and peripheral anionic site (PAS) of both AChE and BChE. Furthermore, docking study of compound 5c showed desired interactions of that compound with amino acid residues located in the active and peripheral anionic sites. Compound 5c was also evaluated for its BACE1 inhibitory activity and demonstrated IC 50 = 76.78 μM. Finally, neuroprotectivity of compound 5c on Aβ-treated neurotoxicity in PC12 cells depicted low activity.

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

Section: Ache and Bche Inhibition Assaymentioning

confidence: 99%

“…In this respect, design, synthesis, and biological evaluation of multi-target heterocycles have been the center of attention to develop potent and novel anti-AD drugs [10 -12] as well as diagnostic applications. [13,14] Focusing on the cholinesterase inhibitory activity of heterocycles, design and synthesis of a wide range of compounds such as coumarins, [15] 1,2,3-triazoles, [16][17][18][19] isoxazoles, [19,20] imidazoles, [21] pyrazoles, [22] and quinazolines, [23] etc., have been developed. In this work, following anti-ChE activity of our previously reported isoxazole derivatives A and B, [19,20] synthesis and biological evaluation of novel isoxazoles connected to phenylpiperazine moiety were reported ( Figure 2).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Design and Synthesis of Selective Acetylcholinesterase Inhibitors: Arylisoxazole‐Phenylpiperazine Derivatives

Saeedi

Mohtadi-Haghighi

Mirfazli

et al. 2019

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Synthesis and Biological Activity of Some Benzochromenoquinolinones: Tacrine Analogs as Potent Anti‐Alzheimer's Agents

Mahdavi

Hariri

Mirfazli

et al. 2019

Alzheimer's disease (AD) is a well‐known neurodegenerative disorder affecting millions of old people worldwide and the corresponding epidemiological data emphasize the importance of the disease. As AD is a multifactorial illness, various single target directed drugs that have reached clinical trials have failed. Therefore, various factors associated with outset of AD have been considered in targeted drug discovery. In this work, various benzochromenoquinolinones were synthesized and evaluated for their cholinesterase and BACE1 inhibitory activities as well as neuroprotective and metal‐chelating properties. Among the synthesized compounds, 14‐amino‐13‐(3‐nitrophenyl)‐2,3,4,13‐tetrahydro‐1H‐benzo[6,7]chromeno[2,3‐b]quinoline‐7,12‐dione (6m) depicted the best inhibitory activity toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with IC50s of 0.86 and 6.03 μm, respectively. Also, the compound could inhibit β‐secretase 1 (BACE1) with IC50=19.60 μm and showed metal chelating ability toward Cu2+, Fe2+, and Zn2+. In addition, docking study demonstrated desirable interactions of compound 6m with amino acid residues characterizing AChE, BChE, and BACE1.

Design and Synthesis of Novel Arylisoxazole‐Chromenone Carboxamides: Investigation of Biological Activities Associated with Alzheimer's Disease

Saeedi

Rastegari

Hariri

et al. 2020

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IranThis article is dedicated to the memory of our unique teacher in Chemistry and Medicinal Chemistry, Professor Abbas Shafiee (1937 -2016).A novel series of hybrid arylisoxazole-chromenone carboxamides were designed, synthesized, and evaluated for their cholinesterase (ChE) inhibitory activity based on the modified Ellman's method. Among synthesized compounds, 5-(3-nitrophenyl)-N-{4-[(2-oxo-2H-1-benzopyran-7-yl)oxy]phenyl}-1,2-oxazole-3-carboxamide depicted the most acetylcholinesterase (AChE) inhibitory activity (IC 50 = 1.23 μM) and 5-(3-chlorophenyl)-N-{4-[(2oxo-2H-1-benzopyran-7-yl)oxy]phenyl}-1,2-oxazole-3-carboxamide was found to be the most potent butyrylcholinesterase (BChE) inhibitor (IC 50 = 9.71 μM). 5-(3-Nitrophenyl)-N-{4-[(2-oxo-2H-1-benzopyran-7-yl)oxy]phenyl}-1,2oxazole-3-carboxamide was further investigated for its BACE1 inhibitory activity as well as neuroprotectivity and metal chelating ability as important factors involved in onset and progress of Alzheimer's disease. It could inhibit BACE1 by 48.46 % at 50 μM. It also showed 6.4 % protection at 25 μM and satisfactory chelating ability toward Zn 2 + , Fe 2 + , and Cu 2 + ions. Docking studies of 5-(3-nitrophenyl)-N-{4-[(2-oxo-2H-1-benzopyran-7-yl)oxy]phenyl}-1,2-oxazole-3-carboxamide and 5-(3-chlorophenyl)-N-{4-[(2-oxo-2H-1-benzopyran-7-yl)oxy]phenyl}-1,2-oxazole-3carboxamide confirmed desired interactions with those amino acid residues of the AChE and BChE, respectively.