Synthesis, molecular modeling and cholinesterase inhibitory effects of 2-indolinone-based hydrazinecarbothioamides

Background: 2-Indolinone-based hydrazinecarbothioamides carrying a 3-phenylsulfonamide moiety (7–9) were designed by replacement of donepezil's pharmacophore group indanone with a 2-indolinone ring. Method: Compounds 7–9 were synthesized by reaction of N-(3-sulfamoylphenyl)hydrazinecarbothioamide (6) with 1 H-indolin-2,3-diones (1–3). Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory effects of compounds 7–9 were assayed. Molecular modeling studies of 5-chloro-1,7-dimethyl-substituted compound 8e were carried out to determine the possible binding interactions at the active site of AChE. Results: Compound 8e showed the strongest inhibition against AChE ( Ki = 0.52 ± 0.11 μM) as well as the highest selectivity (SI = 37.69). The selectivity for AChE over BuChE of compound 8e was approximately 17-times higher than donepezil and 26-times higher than galantamine. Conclusion: Further development of compounds 7–9 may present new promising agents for Alzheimer's treatment.

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Structural basis of fullerene derivatives as novel potent inhibitors of protein acetylcholinesterase without catalytic active site interaction: insight into the inhibitory mechanism through molecular modeling studies

Journal of Biomolecular Structure and Dynamics ◽

10.1080/07391102.2019.1576543 ◽

2019 ◽

Vol 38 (2) ◽

pp. 410-425 ◽

Cited By ~ 7

Author(s):

Yongfeng Wan ◽

Shanshan Guan ◽

Mengdan Qian ◽

Houhou Huang ◽

Fei Han ◽

...

Keyword(s):

Molecular Modeling ◽

Active Site ◽

Structural Basis ◽

Inhibitory Mechanism ◽

Fullerene Derivatives ◽

Modeling Studies ◽

Catalytic Active Site ◽

Molecular Modeling Studies ◽

Insight Into

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Stereochemistry of the chloroperoxidase active site: crystallographic and molecular-modeling studies

Chemistry & Biology ◽

10.1016/s1074-5521(98)90003-5 ◽

1998 ◽

Vol 5 (9) ◽

pp. 461-473 ◽

Cited By ~ 116

Author(s):

M. Sundaramoorthy ◽

James Terner ◽

Thomas L. Poulos

Keyword(s):

Molecular Modeling ◽

Active Site ◽

Modeling Studies ◽

Molecular Modeling Studies

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Molecular modeling studies on the urease active site and the enzyme-catalyzed urea hydrolysis

Journal of Computer-Aided Molecular Design ◽

10.1007/bf00117401 ◽

1990 ◽

Vol 4 (4) ◽

pp. 355-367 ◽

Cited By ~ 6

Author(s):

Ramiro Medina ◽

Klaus M�ller

Keyword(s):

Molecular Modeling ◽

Active Site ◽

Urea Hydrolysis ◽

Modeling Studies ◽

Molecular Modeling Studies

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Active Site Structure of Rieske-Type Proteins: Electron Nuclear Double Resonance Studies of Isotopically Labeled Phthalate Dioxygenase fromPseudomonas cepaciaand Rieske Protein fromRhodobacter capsulatusand Molecular Modeling Studies of a Rieske Center†,‡

Biochemistry ◽

10.1021/bi960380u ◽

1996 ◽

Vol 35 (24) ◽

pp. 7834-7845 ◽

Cited By ~ 35

Author(s):

Ryszard J. Gurbiel ◽

Peter E. Doan ◽

George T. Gassner ◽

Thomas J. Macke ◽

David A. Case ◽

...

Keyword(s):

Molecular Modeling ◽

Active Site ◽

Double Resonance ◽

Rieske Protein ◽

Electron Nuclear Double Resonance ◽

Site Structure ◽

Modeling Studies ◽

Molecular Modeling Studies ◽

Active Site Structure

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Importance of the hydroxyl substituents in the B–ring of plant flavonols on their preferential binding interactions with VEGF G–quadruplex DNA: Multi-spectroscopic and molecular modeling studies

International Journal of Biological Macromolecules ◽

10.1016/j.ijbiomac.2018.06.115 ◽

2018 ◽

Vol 118 ◽

pp. 629-639 ◽

Cited By ~ 7

Author(s):

Snehasish Bhattacharjee ◽

Sandipan Chakraborty ◽

Erik Chorell ◽

Pradeep K. Sengupta ◽

Sudipta Bhowmik

Keyword(s):

Molecular Modeling ◽

Binding Interactions ◽

Quadruplex Dna ◽

Modeling Studies ◽

G Quadruplex ◽

Preferential Binding ◽

Molecular Modeling Studies

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Design, synthesis, and molecular modeling studies of 5′-deoxy-5′-ureidoadenosine: 5′-ureido group as multiple hydrogen bonding donor in the active site of S-adenosylhomocysteine hydrolase

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2007.06.013 ◽

2007 ◽

Vol 17 (16) ◽

pp. 4456-4459 ◽

Cited By ~ 8

Author(s):

Ting Wang ◽

Hyun Joo Lee ◽

Dilip K. Tosh ◽

Hea Ok Kim ◽

Shantanu Pal ◽

...

Keyword(s):

Hydrogen Bonding ◽

Molecular Modeling ◽

Active Site ◽

Design Synthesis ◽

Adenosylhomocysteine Hydrolase ◽

Modeling Studies ◽

Molecular Modeling Studies ◽

Multiple Hydrogen Bonding

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Molecular modeling studies of the binding modes of aldose reductase inhibitors at the active site of human aldose reductase

Bioorganic & Medicinal Chemistry ◽

10.1016/s0968-0896(98)00139-4 ◽

1998 ◽

Vol 6 (10) ◽

pp. 1811-1819 ◽

Cited By ~ 37

Author(s):

Yong S Lee ◽

Zhou Chen ◽

Peter F Kador

Keyword(s):

Molecular Modeling ◽

Aldose Reductase ◽

Active Site ◽

Binding Modes ◽

Aldose Reductase Inhibitors ◽

Reductase Inhibitors ◽

Modeling Studies ◽

Molecular Modeling Studies

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Indole-Based Hydrazones Containing A Sulfonamide Moiety as Selective Inhibitors of Tumor-Associated Human Carbonic Anhydrase Isoforms IX and XII

International Journal of Molecular Sciences ◽

10.3390/ijms20092354 ◽

2019 ◽

Vol 20 (9) ◽

pp. 2354 ◽

Cited By ~ 3

Author(s):

Kübra Demir-Yazıcı ◽

Silvia Bua ◽

Nurgül Mutlu Akgüneş ◽

Atilla Akdemir ◽

Claudiu T. Supuran ◽

...

Keyword(s):

Molecular Modeling ◽

Carbonic Anhydrase ◽

Enzyme Inhibition ◽

Active Sites ◽

Selective Inhibitors ◽

Binding Interactions ◽

Modeling Studies ◽

Molecular Modeling Studies ◽

Human Carbonic Anhydrase

Novel sulfonamidoindole-based hydrazones with a 2-(hydrazinocarbonyl)-3-phenyl-1H-indole-5-sulfonamide scaffold were synthesized and tested in enzyme inhibition assays against the tumor-associated carbonic anhydrase isoforms, hCA IX and XII, and the off-targets, hCA I and II. The compounds showed selectivity against hCA IX and XII over hCA I and II. Six compounds showed KI values lower than 10 nM against hCA IX or XII. Molecular modeling studies were performed to suggest binding interactions between the ligand and the hCA active sites.

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