Design, synthesis and evaluation of imidazo[1,2-a]pyrazin-8(7H)-one derivatives as acetylcholinesterase inhibitors and antioxidants DOI Creative Commons

Wen-Rong Du,

Ben-Ben Wei,

Xin-Yuan Guo

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: June 24, 2024

Abstract A series of 8-(piperazin-1-yl)imidazo[1,2-a]pyrazine derivatives were designed and synthesized as acetylcholinesterase inhibitors (AChEIs) antioxidants for the treatment Alzheimer's disease (AD). Moreover, biological evaluation results demonstrated that these compounds exhibited moderate inhibitory activities toward (AChE) radical scavenging activities. Among them, compound 14r was most potent AChE inhibitor with an IC50 value 0.47 µM activity against butyrylcholinesterase (BuChE) (IC50 = 11.02 µM). Meanwhile had best selectivity index (SI) values 23.45. Compound has better well compared to reference drug galantamine (AChE 5.01 µM, BuChE 18.46 SI 3.68). 14o antioxidant 89.33 which lower than ascorbic acid 25.70 µM) control drug. Furthermore, molecular docking studies indicated could simultaneously bind both catalytic active site peripheral anionic AChE, consistent mixed inhibition pattern shown by enzyme kinetic studies. The interaction’s stability 14r-AChE/BuChE also assessed using a conventional atomistic 100 ns dynamics simulation study, revealed conformational representative in cavity AChE. In addition, properties all predicted online through SwissADME, matched orally administered drugs. Based on properties, AChEI valuable further development.

Language: Английский

Practical Three-Component Regioselective Synthesis of Drug-Like 3-Aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines as Potential Non-Covalent Multi-Targeting Inhibitors To Combat Neurodegenerative Diseases DOI
Hossein Mousavi, Mehdi Rimaz, Behzad Zeynizadeh

et al.

ACS Chemical Neuroscience, Journal Year: 2024, Volume and Issue: 15(9), P. 1828 - 1881

Published: April 22, 2024

Neurodegenerative diseases (NDs) are one of the prominent health challenges facing contemporary society, and many efforts have been made to overcome (or) control it. In this research paper, we described a practical one-pot two-step three-component reaction between 3,4-dihydronaphthalen-1(2H)-one (1), aryl(or heteroaryl)glyoxal monohydrates (2a–h), hydrazine monohydrate (NH2NH2•H2O) for regioselective preparation some 3-aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnoline derivatives (3a–h). After synthesis characterization mentioned cinnolines (3a–h), in silico multi-targeting inhibitory properties these heterocyclic scaffolds investigated upon various Homo sapiens-type enzymes, including hMAO-A, hMAO-B, hAChE, hBChE, hBACE-1, hBACE-2, hNQO-1, hNQO-2, hnNOS, hiNOS, hPARP-1, hPARP-2, hLRRK-2(G2019S), hGSK-3β, hp38α MAPK, hJNK-3, hOGA, hNMDA receptor, hnSMase-2, hIDO-1, hCOMT, hLIMK-1, hLIMK-2, hRIPK-1, hUCH-L1, hPARK-7, hDHODH, which confirmed their functions roles neurodegenerative (NDs), based on molecular docking studies, obtained results were compared with wide range approved drugs well-known (with IC50, EC50, etc.) compounds. addition, ADMET prediction analysis was performed examine prospective drug synthesized compounds The from studies ADMET-related data demonstrated that series heteroaryl)-5,6-dihydrobenzo[h]cinnolines especially hit ones, can really be turned into potent core new treatment and/or due having reactionable locations, they able further organic reactions (such as cross-coupling reactions), expansion (for example, using other types monohydrates) makes avenue designing novel efficient purpose.

Language: Английский

Citations

9
Promising thiazolidinedione-thiazole based multi-target and neuroprotective hybrids for Alzheimer’s disease: Design, synthesis, in-vitro, in-vivo and in-silico studies DOI
Fahad Hussain, Ayesha Tahir, Hafiz Muzzammel Rehman

et al.

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 287, P. 117327 - 117327

Published: Feb. 3, 2025

Language: Английский

Citations

1
In Silico Study, Synthesis, and In Vitro Evaluation of Acetylcholinesterase and Butyrylcholinesterase Inhibitory Activity of Novel N‐Thiazole Substituted Acetamide Coumarin Derivatives DOI Open Access
Pooja Patowary, Anshul Shakya,

Surajit Kumar Ghosh

et al.

Chemistry & Biodiversity, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 4, 2025

In this study, a structurally directed pharmacophore hybridization technique is used to combine the two essential structural scaffolds coumarin and thiazoles in search of new class acetylcholinesterase (AChE) butyrylcholinesterase (BuChE) inhibitor for Alzheimer's disease (AD). A library 120 compounds was designed series 5a(1-15), 5b(16-30), 5c(31-45), 5d(46-60), 6a(61-75), 6b(76-90), 6c(91-105), 6d(106-120) using various substituted phenol, β-ketoesters, thiazole derivatives. Eleven were identified as potential hybrids molecular property filter analysis docking studies, they comprise N-substituted The results indicated that 5b16 5c35 exhibited strong binding interactions with GLY116, GLY117, TYR332, HIS438 (ranging from -27.42 -24.18 kcal/mol) GLY119, ASP72, PHE288 -32.21 -25.92 when tested against AChE (1EVE) BuChE (1P0I) inhibitors. These synthesized via conventional methods characterized by different spectroscopic methods. vitro anti-cholinesterase activity compounds, example, showed potent moderate IC50 (2.00 ± 0.09-29.63 0.48) µM (34.93 0.62-17.92 0.42) µM, respectively. Our study demonstrated development novel hybrid derivatives inhibitors, these could be utilized ADs.

Language: Английский

Citations

1
“Triazole-linked thiazolidinedione-Benzothiazole hybrids: Design and biological evaluation as AChE inhibitors” DOI
Aya M. Almatary, Mohammad M. Al‐Sanea,

Eman E. Nasr

et al.

Bioorganic Chemistry, Journal Year: 2025, Volume and Issue: 157, P. 108295 - 108295

Published: Feb. 21, 2025

Language: Английский

Citations

1
Latest advances in dual inhibitors of acetylcholinesterase and monoamine oxidase B against Alzheimer’s disease DOI Creative Commons

Da-Jiang Zou,

Renzheng Liu,

Yangjing Lv

et al.

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 38(1)

Published: Nov. 13, 2023

Alzheimer's disease (AD) is a progressive brain characterised by memory loss and cognition impairment, ultimately leading to death. There are three FDA-approved acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine, AChEIs) for the symptomatic treatment of AD. Monoamine oxidase B (MAO-B) has been considered contribute pathologies Therefore, we reviewed dual (AChE) MAO-B developed in last five years. In this review, these dual-target were classified into six groups according basic parent structure, including chalcone, coumarin, chromone, benzo-fused five-membered ring, imine hydrazine, other scaffolds. Their design strategies, structure-activity relationships (SARs), molecular docking studies with AChE analysed discussed, giving valuable insights subsequent development inhibitors. Challenges balanced potent noted, corresponding solutions provided.

Language: Английский

Citations

22
Indole Derivatives Bearing Imidazole, Benzothiazole-2-Thione or Benzoxazole-2-Thione Moieties—Synthesis, Structure and Evaluation of Their Cytoprotective, Antioxidant, Antibacterial and Fungicidal Activities DOI Creative Commons
Beata Jasiewicz, Karolina Babijczuk, Beata Warżajtis

et al.

Molecules, Journal Year: 2023, Volume and Issue: 28(2), P. 708 - 708

Published: Jan. 10, 2023

In the search for new bioactive compounds, a methodology based on combining two molecules with biological properties into hybrid molecule was used to design and synthesize of series ten indole derivatives bearing imidazole, benzothiazole-2-thione, or benzoxazole-2-thione moieties at C-3 position. The compounds were spectroscopically characterized tested their antioxidant, antibacterial, fungicidal activities. crystal structures determined five them. Comparison closely related containing either benzothiazole-2-thione clearly shows that replacement -S- -O- ring atoms modify molecular conformation in crystal, changes intermolecular interactions, has severe impact activity. results indicate indole-imidazole alkyl substituent exhibit an excellent cytoprotective effect against AAPH-induced oxidative hemolysis act as effective ferrous ion chelating agents. compound chlorine inhibited growth fungal strains: Coriolus versicolor (Cv), Poria placenta (Pp), Coniophora puteana (Cp), Gloeophyllum trabeum (Gt). showed highest antibacterial activity, which largest growth-inhibition zones noted M. luteus P. fluorescens cultures. obtained may be helpful development selective antioxidants and/or antimicrobial

Language: Английский

Citations

15
In Silico and in Vitro Biological Evaluation of Novel Serial Sulfonate Derivatives on Pancreatic Lipase Activity DOI
Fuat YETİŞSİN, Adem Korkmaz, Esin Kaya

et al.

Chemistry & Biodiversity, Journal Year: 2023, Volume and Issue: 20(11)

Published: Sept. 25, 2023

The novel benzothiazole sulfonate hybrid derivatives containing azomethine group were synthesized and characterized using 1 H-NMR, 13 C-NMR, HR-MS analysis. potential enzyme inhibition activities against pancreatic lipase of the screened with in vitro silico methods. IC50 values compounds 5 b (23.89 μM), i (28.87 f (30.13±4.32) found to be more effective inhibitors than orlistat (57.75 μM) studies. Also, binding affinities (-8.7 kcal/mol), (-8.6 (-8.9 kcal/mol) for In addition, absorption distribution, metabolism, excretion properties (ADME), molecular properties, toxicity estimation, bioactivity scores scanned. It was have ability cross brain-blood barrier a, b, c, d. All calculated taken orally as drugs, suitable intestinal tract not carcinogenic, well very strongly bound plasma proteins. Finally, compound observed best inhibitor according

Language: Английский

Citations

13
Recent Advances in The Therapeutic Insights of Thiazole Scaffolds as Acetylcholinesterase Inhibitors DOI
Dina H. Dawood, Manal M. Anwar

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 117331 - 117331

Published: Jan. 1, 2025

Language: Английский

Citations

0
A multi enzyme study reviewing the role of target enzymes in Alzheimer’s disease and unveiling potential inhibitors with insights on their present and future assessment DOI
Sanaa Zaki, Samiullah Khan, Ruhi Ali

et al.

Medicinal Chemistry Research, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 31, 2025

Language: Английский

Citations

0
Development of Donor–Acceptor Architecture-Based Potential Theranostic Fluorescent Probes for Alzheimer’s Disease DOI
Nilesh Gajanan Bajad,

Gajendra T.A.,

Khushboo Sharma

et al.

ACS Chemical Neuroscience, Journal Year: 2025, Volume and Issue: unknown

Published: March 19, 2025

The cholinergic deficits and deposition of β-amyloid (Aβ) species are regarded as the key events contributing to progression Alzheimer's disease (AD). Herein, a series novel donor-acceptor architecture-type potential theranostic agents were designed, synthesized, evaluated for their against cholinesterase (ChE) enzymes detection Aβ species, which primary targets in development therapeutics AD. optimal compound/probe 18 containing benzothiazolium fluorophore with bifunctional electron-donating N-aryl piperazine scaffold exhibited potent inhibitory activities acetylcholinesterase (AChE; IC50 = 0.172 ± 0.011 μM) butyrylcholinesterase (BuChE; 1.376 0.141 μM). Measurement fluorescence properties showed that probe emission maxima (λem) >610 nm dimethyl sulfoxide (DMSO) >590 PBS, suitable imaging. In vitro studies demonstrated change characteristics high binding affinities (18; Kd 0.731 upon aggregates. affinity toward aggregates was further observed elavGAL4 > UAS Aβ, Drosophila larval brain sections, using imaging technique. vivo acute oral toxicity evaluation indicated safety profile lead 18. Moreover, behavioral including Y-maze object recognition tests signified administration compound improved cognitive spatial memory impairment at dose 10 20 mg/kg scopolamine-induced deficit model.

Language: Английский

Citations

0