Design, synthesis and molecular modeling of isothiochromanone derivatives as acetylcholinesterase inhibitors

Aim: A series of novel isothio- and isoselenochromanone derivatives bearing N-benzyl pyridinium moiety were designed, synthesized and evaluated as acetylcholinesterase (AChE) inhibitors. Results: Most of the target compounds exhibited potent anti-AChE activities with IC50 values in nanomolar ranges. Among them, compound 15a exhibited the most potent anti-AChE activity (IC50 = 2.7 nM), moderate antioxidant activity and low neurotoxicity. Moreover, the kinetic and docking studies revealed that compound 15a was a mixed-type inhibitor, which bounds to peripheral anionic site and catalytic active site of AChE. Conclusion: Those results suggested that compound 15a might be a potential candidate for AD treatment.

Download Full-text

Synthesis and antimicrobial activity of aryldiazenyl/arylhydrazono pyrazoles

Journal of Chemical Research ◽

10.1177/17475198211057461 ◽

2021 ◽

Vol 45 (11-12) ◽

pp. 1093-1099

Author(s):

Abdulrhman Alsayari ◽

Yahya I Asiri ◽

Abdullatif Bin Muhsinah ◽

Mohd. Zaheen Hassan

Keyword(s):

Active Site ◽

Phenyl Ring ◽

Antimicrobial Agents ◽

Inhibitory Concentration ◽

Docking Studies ◽

Considerable Effect ◽

Design Synthesis ◽

Structure Activity ◽

Antimicrobial Evaluation

We report the design, synthesis, and in vitro antimicrobial evaluation of functionalized pyrazoles containing a hydrazono/diazenyl moiety. Among these newly synthesized derivatives, 4-[2-(4-chlorophenyl)hydrazono]-5-methyl-2-[2-(naphthalen-2-yloxy)acetyl]-2,4-dihydro-3 H-pyrazol-3-one is a promising antimicrobial agent against Staphylococcus aureus (minimum inhibitory concentration 0.19 μg mL−1). Structure–activity relationship studies reveal that the electronic environment on the distal phenyl ring has a considerable effect on the antimicrobial potential of the hybrid analogues. Molecular docking studies into the active site of S. aureus dihydrofolate reductase also prove the usefulness of hybridizing a pyrazole moiety with azo and hydrazo groups in the design of new antimicrobial agents.

Download Full-text

Galantamine-Curcumin Hybrids as Dual-Site Binding Acetylcholinesterase Inhibitors

Molecules ◽

10.3390/molecules25153341 ◽

2020 ◽

Vol 25 (15) ◽

pp. 3341

Author(s):

Georgi Stavrakov ◽

Irena Philipova ◽

Atanas Lukarski ◽

Mariyana Atanasova ◽

Dimitrina Zheleva ◽

...

Keyword(s):

Amyloid Beta ◽

Ache Activity ◽

Combinatorial Library ◽

Acetylcholinesterase Inhibitors ◽

Aβ Oligomers ◽

Ache Inhibitors ◽

Adme Properties ◽

Dual Site ◽

Site Binding

Galantamine (GAL) and curcumin (CU) are alkaloids used to improve symptomatically neurodegenerative conditions like Alzheimer’s disease (AD). GAL acts mainly as an inhibitor of the enzyme acetylcholinesterase (AChE). CU binds to amyloid-beta (Aβ) oligomers and inhibits the formation of Aβ plaques. Here, we combine GAL core with CU fragments and design a combinatorial library of GAL-CU hybrids as dual-site binding AChE inhibitors. The designed hybrids are screened for optimal ADME properties and BBB permeability and docked on AChE. The 14 best performing compounds are synthesized and tested in vitro for neurotoxicity and anti-AChE activity. Five of them are less toxic than GAL and CU and show activities between 41 and 186 times higher than GAL.

Download Full-text

Structure—activity relationships for in vitro oxime reactivation of chlorpyrifos-inhibited acetylcholinesterase

Chemical Papers ◽

10.2478/s11696-007-0030-7 ◽

2007 ◽

Vol 61 (4) ◽

Cited By ~ 3

Author(s):

K. Kuča ◽

V. Račáková ◽

D. Jun

Keyword(s):

Biological Activity ◽

Active Site ◽

Ache Activity ◽

Chemical Structure ◽

Organophosphorus Pesticides ◽

Ache Inhibitors ◽

Structure Activity ◽

The Relationship ◽

Representative Member

AbstractOrganophosphorus pesticides parathion, chlorpyrifos, and malathion inhibit the enzyme acetylcholinesterase (AChE; EC 3.1.1.7) via phosphorylation of its active site. AChE reactivators and anticholinergics are compounds used as antidotes in the case of intoxication by these AChE inhibitors. In this work, chlorpyrifos, a representative member of this pesticide family, was used to inhibit the AChE activity of rat brain. The effect of twenty-one structurally different AChE reactivators was tested in vitro and subsequently, the relationship between their chemical structure and biological activity was outlined.

Download Full-text

Discovery of Novel Acetylcholinesterase Inhibitors as Potential Candidates for the Treatment of Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms20041000 ◽

2019 ◽

Vol 20 (4) ◽

pp. 1000 ◽

Cited By ~ 5

Author(s):

Minky Son ◽

Chanin Park ◽

Shailima Rampogu ◽

Amir Zeb ◽

Keun Lee

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Active Site ◽

Neurodegenerative Disorder ◽

3D Qsar ◽

Pharmacophore Modeling ◽

Huperzine A ◽

Potential Candidate ◽

Binding Modes ◽

Ache Inhibitors

Acetylcholinesterase (AChE) catalyzes the hydrolysis of neurotransmitter acetylcholine to acetate and choline in a synaptic cleft. Deficits in cholinergic neurotransmitters are linked closely with the progression of Alzheimer’s disease (AD), which is a neurodegenerative disorder characterized by memory impairment, and a disordered cognitive function. Since the previously approved AChE inhibitors, donepezil (Aricept), galantamine (Reminyl), and rivastigmine (Exelon), have side effects and several studies are being carried out out to develop novel AD drugs, we have applied a three-dimensional quantitative structure−activity relationship (3D QSAR) and structure-based pharmacophore modeling methodologies to identify potential candidate inhibitors against AChE. Herein, 3D QSAR and structure-based pharmacophore models were built from known inhibitors and crystal structures of human AChE in complex with donepezil, galantamine, huperzine A, and huprine W, respectively. The generated models were used as 3D queries to screen new scaffolds from various chemical databases. The hit compounds obtained from the virtual screening were subjected to an assessment of drug-like properties, followed by molecular docking. The final hit compounds were selected based on binding modes and molecular interactions in the active site of the enzyme. Furthermore, molecular dynamics simulations for AChE in complex with the final hits were performed to evaluate that they maintained stable interactions with the active site residues. The binding free energies of the final hits were also calculated using molecular mechanics/Poisson-Boltzmann surface area method. Taken together, we proposed that these hits can be promising candidates for anti-AD drugs.

Download Full-text

Pyrazolobenzothiazine-based carbothioamides as new structural leads for the inhibition of monoamine oxidases: design, synthesis, in vitro bioevaluation and molecular docking studies

MedChemComm ◽

10.1039/c6md00570e ◽

2017 ◽

Vol 8 (2) ◽

pp. 452-464 ◽

Cited By ~ 10

Author(s):

Syed Mobasher Ali Abid ◽

Sana Aslam ◽

Sumera Zaib ◽

Syeda Mahwish Bakht ◽

Matloob Ahmad ◽

...

Keyword(s):

Molecular Docking ◽

Active Site ◽

Potent Inhibitor ◽

Binding Mode ◽

Docking Studies ◽

Design Synthesis ◽

Molecular Docking Studies ◽

Monoamine Oxidases ◽

Mao B

Binding mode of potent inhibitor (green) & cognate ligand (pink) in the active site of MAO-B.

Download Full-text

MOLECULAR DOCKING STUDY ON 1-(3-(4-BENZYLPIPERAZIN-1-YL)PROPYL)-3,7-DIMETHYL-1H-PURINE-2,6(3H,7H)-DIONE AS AN ACETYLCHOLINESTERASE INHIBITOR

CBU International Conference Proceedings ◽

10.12955/cbup.v6.1268 ◽

2018 ◽

Vol 6 ◽

pp. 898-903

Author(s):

Maria Hristova ◽

Mariyana Atanasova ◽

Iva Valkova ◽

Lilya Andonova ◽

Irini Doytchinova ◽

...

Keyword(s):

Active Site ◽

Acetylcholinesterase Inhibitor ◽

Docking Study ◽

Binding Mode ◽

New Drugs ◽

Ache Inhibition ◽

Molecular Docking Study ◽

Ache Inhibitors ◽

Good Target ◽

Catalytic Active Site

Acetylcholinesterase (AChE) is a good target in the design of new drugs for the treatment of Alzheimer’s disease. The currently known drugs -donepezil, galantamine and rivastignime- act as moderate AChE inhibitors. In the present study, we docked a newly synthesized arylpiperazine derivative 1-(3-(4-benzylpiperazin-1-yl)propyl)-3,7-dimethyl-1H-purine-2,6(3H,7H)-dione (LA1) into rhAChE and identified its binding mode. The docking pose of the studied LA1 molecule depends of the protonated state of the nitrogen atom of the piperazine moiety where in the best scored poses, the xanthine moiety of LA1 is bound into the catalytic active site (CAS) of AChE, while the arylpiperazine fragment is placed into the peripheral binding site (PAS). The Ellman’s test confirmed the compound binding. LA1 has good permeability through the GIT and BBB assessed by PAMPA. LA1 is a prospective lead for AChE inhibition.

Download Full-text

Exploration of Active Site-Directed Plasmin Inhibitors: Beyond Tranexamic Acid

Processes ◽

10.3390/pr9020329 ◽

2021 ◽

Vol 9 (2) ◽

pp. 329

Author(s):

Yuko Tsuda ◽

Koushi Hidaka ◽

Keiko Hojo ◽

Yoshio Okada

Keyword(s):

Tranexamic Acid ◽

Active Site ◽

Docking Studies ◽

Potential Candidate ◽

Activity Structure ◽

Anti Cancer ◽

Structure Relationship ◽

Plasmin Inhibitors ◽

Cancer Agent ◽

Relationship Of

Plasmin (Plm), a trypsin-like serine protease, is responsible for fibrinolysis pathway and pathologic events, such as angiogenesis, tumor invasion, and metastasis, and alters the expression of cytokines. A growing body of data indicates that a Plm inhibitor is a potential candidate as an anti-inflammatory and anti-cancer agent. A class of active site-directed plasmin inhibitors containing tranexamic acid residue has been designed. As evidenced by docking studies, the inhibitor binds to the active site not to the lysine binding site (LBS) in plasmin, thus preventing plasmin from digesting the substrate. Further optimization of the series, concerning both activity and selectivity, led to the second generation of inhibitors. This review focuses on the Plm inhibitory activity-structure relationship of Plm inhibitors with the goal of realizing their design and clinical application.

Download Full-text

Synthesis, Crystal Structure and Biological Evaluation of Novel 2-Phenylthiazole Derivatives as Multi-Targeting Agents to Treat Alzheimer's Disease

Journal of Chemical Research ◽

10.3184/174751917x15045169836217 ◽

2017 ◽

Vol 41 (9) ◽

pp. 551-555 ◽

Cited By ~ 1

Author(s):

Da-Hua Shi ◽

Zong-Ming Tang ◽

Xiao-Dong Ma ◽

Wei Min ◽

Xiang-Jian Xu ◽

...

Keyword(s):

Active Site ◽

Docking Study ◽

Biological Evaluation ◽

Acetylcholinesterase Inhibition ◽

Cholinesterase Inhibition ◽

Spectroscopic Techniques ◽

X Ray Diffraction ◽

Anionic Site ◽

X Ray ◽

Catalytic Active Site

Three novel 2-phenylthiazole derivatives were synthesised and characterised by spectroscopic techniques. The structure of the synthesised compounds was unambiguously confirmed by a single-crystal X-ray diffraction analysis of ethyl 2-(4-{[5-(4-benzylpiperidin-1-yl)pentyl]oxy}phenyl)thiazole-4-carboxylate. All of the compounds presented good cholinesterase-inhibition activities and ethyl 2-(4-{[5-(4-benzylpiperidin-1-yl)pentyl]oxy}phenyl)thiazole-4-carboxylate showed the best acetylcholinesterase-inhibition and butyrylcholinesterase-inhibition abilities with IC50 values of 5.19 μM and 5.83 μM. The docking study demonstrated that it could interact with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of acetylcholinesterase and could chelate with metal ions like Cu2+ and Zn2+.

Download Full-text

Synthesis, Biological Evaluation, and In Silico Studies of New Acetylcholinesterase Inhibitors Based on Quinoxaline Scaffold

Molecules ◽

10.3390/molecules26164895 ◽

2021 ◽

Vol 26 (16) ◽

pp. 4895

Author(s):

Paptawan Suwanhom ◽

Jirakrit Saetang ◽

Pasarat Khongkow ◽

Teerapat Nualnoi ◽

Varomyalin Tipmanee ◽

...

Keyword(s):

Inhibitory Activity ◽

In Silico ◽

Acetylcholinesterase Inhibitors ◽

Biological Evaluation ◽

Anionic Site ◽

Human Neuroblastoma ◽

Ache Inhibitors ◽

In Silico Studies ◽

Quinoxaline Derivatives ◽

Ic50 Values

A quinoxaline scaffold exhibits various bioactivities in pharmacotherapeutic interests. In this research, twelve quinoxaline derivatives were synthesized and evaluated as new acetylcholinesterase inhibitors. We found all compounds showed potent inhibitory activity against acetylcholinesterase (AChE) with IC50 values of 0.077 to 50.080 µM, along with promising predicted drug-likeness and blood–brain barrier (BBB) permeation. In addition, potent butyrylcholinesterase (BChE) inhibitory activity with IC50 values of 14.91 to 60.95 µM was observed in some compounds. Enzyme kinetic study revealed the most potent compound (6c) as a mixed-type AChE inhibitor. No cytotoxicity from the quinoxaline derivatives was noticed in the human neuroblastoma cell line (SHSY5Y). In silico study suggested the compounds preferred the peripheral anionic site (PAS) to the catalytic anionic site (CAS), which was different from AChE inhibitors (tacrine and galanthamine). We had proposed the molecular design guided for quinoxaline derivatives targeting the PAS site. Therefore, the quinoxaline derivatives could offer the lead for the newly developed candidate as potential acetylcholinesterase inhibitors.

Download Full-text

Comparison of Two Schizophyllum commune Strains in Production of Acetylcholinesterase Inhibitors and Antioxidants from Submerged Cultivation

Journal of Fungi ◽

10.3390/jof7020115 ◽

2021 ◽

Vol 7 (2) ◽

pp. 115

Author(s):

Jovana Mišković ◽

Maja Karaman ◽

Milena Rašeta ◽

Nenad Krsmanović ◽

Sanja Berežni ◽

...

Keyword(s):

Antibacterial Activity ◽

Ache Activity ◽

Phenolic Content ◽

Antioxidative Activity ◽

Fermentation Broth ◽

Schizophyllum Commune ◽

Acetylcholinesterase Inhibitors ◽

Submerged Cultivation ◽

Total Phenolic ◽

Ache Inhibitors

In recent years, fungi have been recognized as producers of acetylcholinesterase (AChE) inhibitors, agents important for the prevention of Alzheimer’s disease (AD). This study aimed to examine the AChE inhibitory, the antioxidative and antibacterial activity of two different Schizophyllum commune strains that originated from Serbia (SRB) and Italy (IT). Submerged cultivation of grown mycelia (M) and fermentation broth (F) of ethanol (EtOH) and polysaccharide (PSH) extracts lasted for 7, 14, 21 and 28 days. For AChE activity Ellman method was performed, while for antioxidative activity, sevendifferent assays were conducted: DPPH, ABTS, FRAP, SOA, OH, NO together with total phenolic content. Antimicrobial screen, LC–MS/MS technique and FTIR measurements were performed. Different isolates exhibited different AChE activity, with PSH being the strongest (SRB, M, 28 days IC90 79.73 ± 26.34 µg/mL), while in EtOH extracts, IT stood out (F, 14 days, IC50 0.8 ± 0.6 µg/mL). PSH extracts (7 days) exhibit significant antioxidative activity (AO), opposite to EtOH extracts where 14 and 21days periods stood out. Only tw extracts showed antibacterial activity. Following LC–MS/MS analysis p-hydroxybenzoic and gallic acids were the most abundant phenolics. PSH extracts demonstrated remarkable results, making this study debut and introducing S. commune as a valuable resource of AChE inhibitors.

Download Full-text