Novel benzoic acid derivatives: Synthesis and biological evaluation as multitarget acetylcholinesterase and carbonic anhydrase inhibitors

Archiv der Pharmazie, Год журнала: 2020, Номер 354(3)

Опубликована: Ноя. 6, 2020

Abstract Alzheimer's disease (AD) is a neurodegenerative disorder characterized by dementia, memory impairment, cognitive dysfunction, and speech impairment. The utility of cholinergic replacement acetylcholinesterase (AChE) inhibitors in AD treatment has been well documented so far. Recently, studies have also evidenced that human carbonic anhydrases (hCAs) serve as an important target for treatment. In this direction, the improvement new multitarget drugs, which can simultaneously modulate several mechanisms or targets included pathway, may be potent strategy to treat AD. light these data understanding developing AD‐related AChE hCAs inhibitors, study, novel methylene‐aminobenzoic acid tetrahydroisoquinolynyl‐benzoic derivatives ( 4a – g 6a ) were designed. synthesized analogs experimentally validated their effects vitro direct enzymatic tests. Also, compounds subjected silico monitoring with Schrödinger Suite software assign binding affinities potential based on Glide XP scoring, molecular mechanics‐generalized Born surface area computing, validation docking. results revealed 6c (1,3‐dimethyldihydropyrimidine‐2,4‐(1 H ,3 )‐dione‐substituted, K I value 33.00 ± 0.29 nM), 6e (cyclohexanone‐substituted, 18.78 0.09 6f (2,2‐dimethyl‐1,3‐dioxan‐4‐one‐substituted, 13.62 0.21 nM) from benzoic series most promising derivatives, they exhibited good multifunctional inhibition at all experimental levels against hCA I, II, AChE, respectively,

Язык: Английский

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Molecular docking and inhibition studies of vulpinic, carnosic and usnic acids on polyol pathway enzymes

Journal of Biomolecular Structure and Dynamics, Год журнала: 2021, Номер 40(22), С. 12008 - 12021

Опубликована: Авг. 23, 2021

Aldose reductase (AR) and sorbitol dehydrogenase (SDH) are important enzymes of the polyol pathway. In current study, inhibitory effects vulpinic acid (VA) carnosic (CA) usnic (UA) on purified AR SDH were determined. These inhibition could be essential to prevent diabetic complications. from sheep kidney. Then, VA, CA UA tested in various concentrations against these activity vitro. KI values found as 1.46 ± 0.04, 5.13 0.25 11.71 0.27 μΜ for UA, respectively, AR. constants 15.32 0.34, 145.60 2.17 213.40 2.64 SDH. findings indicate that useful treatment complications.Communicated by Ramaswamy H. Sarma

Язык: Английский

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Novel inhibitors with sulfamethazine backbone: synthesis and biological study of multi-target cholinesterases and α-glucosidase inhibitors

Journal of Biomolecular Structure and Dynamics, Год журнала: 2021, Номер 40(19), С. 8752 - 8764

Опубликована: Май 5, 2021

The underlying cause of many metabolic diseases is abnormal changes in enzyme activity metabolism. Inhibition enzymes such as cholinesterases (ChEs; acetylcholinesterase, AChE and butyrylcholinesterase, BChE) α-glucosidase (α-GLY) one the accepted approaches treatment Alzheimer's disease (AD) diabetes mellitus (DM). Here we reported an investigation a new series novel ureido-substituted derivatives with sulfamethazine backbone (2a-f) for inhibition AChE, BChE, α-GLY. All demonstrated nanomolar levels α-GLY inhibitors KI values range 56.07-204.95 nM, 38.05-147.04 12.80-79.22 respectively. Among strong N-(4,6-dimethylpyrimidin-2-yl)-4-(3-substitutedphenylureido) benzenesulfonamide detected against ChEs, compound 2c, 4-fluorophenylureido derivative, most potent profile towards BChE. A comprehensive ligand/receptor interaction prediction was performed silico three providing molecular docking using Glide XP, MM-GBSA, ADME-Tox modules. present research reinforces rationale behind utilizing innovative anticholinergic antidiabetic agents mechanism action, submitting propositions rational design synthesis targeting ChEs α-GLY.Communicated by Ramaswamy H. Sarma.

Язык: Английский

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Transition‐Metal Complexes of Bidentate Schiff‐Base Ligands: In Vitro and In Silico Evaluation as Non‐Classical Carbonic Anhydrase and Potential Acetylcholinesterase Inhibitors

ChemistrySelect, Год журнала: 2021, Номер 6(29), С. 7278 - 7284

Опубликована: Авг. 2, 2021

Abstract Schiff bases display superior features for many areas, such as significant intermediates in industrial biological, pharmacological, catalytic and optical properties, organic synthesis, coordination chemistry. The pre‐synthesized two base ligands ( HL 1 2 ) their bidentate metal complexes Co(L , Cu L Ni were tested inhibition activities on acetylcholinesterase (AChE) human carbonic anhydrase h CA I II) isoforms. transition of displayed the potent effect with K constants ranging from 16.39±0.15 to 88.63±0.27 nM 9.32±0.13 33.66±0.57 isoenzymes AChE, respectively. compound AChE II had highest inhibitory effect. Besides, molecular docking analyses most active performed understand binding interactions enzymes’ sites. According both vitro silico analysis results, all compounds potential inhibitors I, isoenzymes.

Язык: Английский

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Novel metabolic enzyme inhibitors designed through the molecular hybridization of thiazole and pyrazoline scaffolds

Archiv der Pharmazie, Год журнала: 2021, Номер 354(12)

Опубликована: Сен. 27, 2021

New hybrid thiazolyl-pyrazoline derivatives (4a-k) were obtained through a facile and versatile synthetic procedure, their inhibitory effects on the human carbonic anhydrase (hCA) isoforms I II as well acetylcholinesterase (AChE) determined. All new thiazolyl-pyrazolines showed activity at nanomolar levels hCA I, II, AChE inhibitors, with KI values in range of 13.35-63.79, 7.01-115.80, 17.89-48.05 nM, respectively. 1-[4-(4-Cyanophenyl)thiazol-2-yl]-3-(4-piperidinophenyl)-5-(4-fluorophenyl)-2-pyrazoline (4f) 1-(4-phenylthiazol-2-yl)-3-(4-piperidinophenyl)-5-(4-fluorophenyl)-2-pyrazoline (4a) against hCAs 1-[4-(4-chlorophenyl)thiazol-2-yl]-3-(4-piperidinophenyl)-5-(4-fluorophenyl)-2-pyrazoline (4d) 1-[4-(4-nitrophenyl)thiazol-2-yl]-3-(4-piperidinophenyl)-5-(4-fluorophenyl)-2-pyrazoline (4b) identified highly potent superior to standard drugs, acetazolamide tacrine, Compounds 4a-k also evaluated for cytotoxic L929 mouse fibroblast (normal) cell line. Moreover, comprehensive ligand-receptor interaction prediction was performed using ADME-Tox, Glide XP, MM-GBSA modules Schrödinger Small-Molecule Drug Discovery Suite elucidate potential binding modes inhibitors these metabolic enzymes.

Язык: Английский

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Sulfonamides incorporating ketene N,S‐acetal bioisosteres as potent carbonic anhydrase and acetylcholinesterase inhibitors

Archiv der Pharmazie, Год журнала: 2020, Номер 353(6)

Опубликована: Апрель 13, 2020

Abstract In this study, 15 novel compounds in a series of sulfonamide‐based ketenes ( 7a – o ) were synthesized and characterized using Fourier‐transform infrared spectroscopy, nuclear magnetic resonance mass spectrometry. All tested for their ability to inhibit the human carbonic anhydrase h CA) isoforms I II, acetylcholinesterase (AChE). The halogen‐appended compounds, 7g , 7o 7i exhibited highest CA I/II AChE inhibition, with K values low nanomolar range = 9.01 ± 0.08, 7.41 0.03, 7.37 0.31 nM, respectively), as compared corresponding parent 2‐[2,2‐dicyano‐1‐(phenylamino)vinylthio]‐ N ‐(4‐sulfamoylphenyl)acetamide analogs . Besides, derivatives 7c 7e selectively inhibited isoform I, whereas 7m 7n II. These findings indicated that all can metabolic dysfunctions, such edema, epilepsy, glaucoma, Alzheimer's disease, by specifically targeting both expression. Herein, also interactions between ligands receptors highlighted through silico molecular docking studies. mechanics–generalized Born surface area method was utilized compute binding free energy contribution critical residues active site estimated. these results would help us perfectly understand relationship activity structural characteristics further improve newly highly effective AChE.

Язык: Английский

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Design, synthesis, and biological activity of novel dithiocarbamate‐methylsulfonyl hybrids as carbonic anhydrase inhibitors

Archiv der Pharmazie, Год журнала: 2022, Номер 355(8)

Опубликована: Май 3, 2022

Abstract Carbonic anhydrase (CA) enzymes are involved in many physiological events. These enzymes, which contain Zn 2+ their structure, can be easily inhibited by dithiocarbamate compounds. In addition, CA enzyme inhibitory activities known groups such as sulfonamide and methylsulfonyl. For this purpose, study, a series of 23 new dithiocarbamate‐methylsulfonyl derivatives were synthesized investigated. The inhibition potentials the obtained compounds against human I II investigated vitro isolation method. It is seen that show activity at nanomolar level. Molecular docking studies carried out silico methods. poses 2a , 2e 2o 2t presented.

Язык: Английский

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A new series of 2,4-thiazolidinediones endowed with potent aldose reductase inhibitory activity

Open Chemistry, Год журнала: 2021, Номер 19(1), С. 347 - 357

Опубликована: Янв. 1, 2021

Abstract In an effort to identify potent aldose reductase (AR) inhibitors, 5-(arylidene)thiazolidine-2,4-diones ( 1 – 8 ), which were prepared by the solvent-free reaction of 2,4-thiazolidinedione with aromatic aldehydes in presence urea, examined for their vitro AR inhibitory activities and cytotoxicity. 5-(2-Hydroxy-3-methylbenzylidene)thiazolidine-2,4-dione 3 ) was most inhibitor this series, exerting uncompetitive inhibition a K i value 0.445 ± 0.013 µM. The IC 50 compound L929 mouse fibroblast cells determined as 8.9 0.66 µM, pointing out its safety inhibitor. Molecular docking studies suggested that exhibited good affinity binding site (PDB ID: 4JIR). Based upon silico absorption, distribution, metabolism, excretion data, is predicted have favorable pharmacokinetic features. Taking into account stands potential orally bioavailable management diabetic complications well nondiabetic diseases.

Язык: Английский

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Biological effects of bis-hydrazone compounds bearing isovanillin moiety on the aldose reductase

Bioorganic Chemistry, Год журнала: 2021, Номер 117, С. 105473 - 105473

Опубликована: Ноя. 8, 2021

Язык: Английский

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Synthesis and characterization of novel acyl hydrazones derived from vanillin as potential aldose reductase inhibitors

Molecular Diversity, Год журнала: 2022, Номер 27(4), С. 1713 - 1733

Опубликована: Сен. 14, 2022

Язык: Английский

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