Design, synthesis, evaluation and molecular modeling studies of some novel N-substituted piperidine-3-carboxylic acid derivatives as potential anticonvulsants

Seth, Ankit; Sharma, Piyoosh; Tripathi, Avanish; Choubey, Priyanka Kumari; Srivastava, Pavan; Tripathi, Prem Prakash; Shrivastava, Sushant K.

doi:10.1007/s00044-018-2141-9

Cited by 33 publications

(12 citation statements)

References 49 publications

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“…To determine the neurotoxic effect of the synthesized potent compounds 31 , 36 , 38 , and 46 , cell viability/cell cytotoxicity-based 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was carried out on the neuroblastoma SH-SY5Y cells according to the literature procedure. , The viability of the cells was determined at various concentrations of 1, 10, 20, and 40 μM of the tested compounds with the corresponding positive control donepezil. The outcomes of the activity showed a negligible reduction in the cell viabilities toward the neuroblastoma cell lines by all of the tested synthesized compounds up to the tested concentration of 40 μM.…”

Section: Resultsmentioning

confidence: 99%

“…Experiments were carried out according to Glassman and White, with some modification. − Briefly, the enzymes COX-1 (10 μL, 0.7–0.8 μg) and COX-2 (300 units/mL) were activated on ice for 5 min with the addition of 50 μL of co-factor solution containing 0.9 mM glutathione, 0.1 mM hematin, and 0.24 mM N , N , N , N -tetramethyl- p -phenylenediamine dihydrochloride (TMPD) in 0.1 M Tris HCl buffer with pH 8.0 for activation. After that, 60 μL of enzyme solution and 20 μL of test samples having various concentrations ranging from 31.25 to 1000 μg/mL were kept at room temperature for 5 min.…”

Section: Methodsmentioning

confidence: 99%

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Structural Modification, In Vitro, In Vivo, Ex Vivo, and In Silico Exploration of Pyrimidine and Pyrrolidine Cores for Targeting Enzymes Associated with Neuroinflammation and Cholinergic Deficit in Alzheimer’s Disease

Javed

Ashraf

Jan

et al. 2021

ACS Chem. Neurosci.

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To obtain a multipotent framework that can target simultaneously COX-2, 5-LOX, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) to treat neuroinflammation, a series of derivatives containing pyrimidine and pyrrolidine cores were rationally synthesized and evaluated. Pyrazoline–pyrimidine hybrid (23g), (3-acetylcoumarin derivative of pyrrolidin-1-yl)benzenesulfonamide (27), and tacrine derivatives of (pyrrolidin-1-yl)benzenesulfonamide (31, 38) displayed excellent in vitro COX-2 inhibition having IC50 value in the nanomolar range. Tacrine–pyrrolidine hybrids 36 and 38, and tacrine–pyrimidine hybrid (46) emerged as the most potent eeAChE inhibitors with IC50 values of 23, 16, and 2 nM, respectively. However, compounds 27, 31, and 38 possessed excellent simultaneous and balanced inhibitory activity against all of the four tested targets and thus emerged as optimal multipotent hybrid compounds among all of the synthesized series of the compounds. In the ex vivo, transgenic animal models treated with compounds 36 and 46 displayed a significant decline in both AChE and BChE potentials in the hippocampus and cortical tissues. In anti-inflammatory activities, animals treated with compounds 36 and 46 displayed a significant % inhibition of edema induced by carrageenan and arachidonic acid. Biochemical analysis and histopathological examination of mice liver indicate that tacrine derivatives are devoid of hepatotoxicity and neurotoxicity against SH-SY5Y neuroblastoma cell lines. In vivo acute toxicity study showed the safety of synthesized compounds up to 1000 mg/kg dose. The inhibitory manner of interaction of these potent drugs on all of the studied in vitro targets was confirmed by molecular docking investigations.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Structural Modification, In Vitro, In Vivo, Ex Vivo, and In Silico Exploration of Pyrimidine and Pyrrolidine Cores for Targeting Enzymes Associated with Neuroinflammation and Cholinergic Deficit in Alzheimer’s Disease

Javed

Ashraf

Jan

et al. 2021

ACS Chem. Neurosci.

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“…The plot between experimental and reported permeability values was constructed, and a threshold limit ( P e > 4.4 × 10 –6 cm s –1 ) was designated for compounds with excellent brain permeability. Permeability values <1.8 × 10 –6 cm s –1 were considered to have poor penetrability and the values in the range (1.8–4.4) × 10 –6 cm s –1 were considered as uncertain permeability. , The results of the PAMPA-BBB assay demonstrated the excellent brain permeability (CNS+) for all the tested compounds 6f , 6g , 10f , 10g , and 10h , with the exception being 13e , which showed uncertain brain permeability (CNS±). The significant brain permeability may be attributed to the presence of lipophilic functional groups (2,4-diCl, 4-CF 3 , and 4-OCF 3 ) at the terminal phenyl group of the compounds.…”

Section: Resultsmentioning

confidence: 99%

Novel Molecular Hybrids of N-Benzylpiperidine and 1,3,4-Oxadiazole as Multitargeted Therapeutics to Treat Alzheimer’s Disease

Sharma

Tripathi

et al. 2019

ACS Chem. Neurosci.

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Multitargeted hybrids of N-benzylpiperidine and substituted 5-phenyl-1,3,4-oxadiazoles were designed, synthesized, and evaluated against Alzheimer's disease (AD). Tested compounds exhibited moderate to excellent inhibition against human acetylcholinesterase (hAChE), butyrylcholinesterase (hBChE), and beta-secretase-1 (hBACE-1). The potential leads 6g and 10f exhibited balanced inhibitory profiles against all the targets, with a substantial displacement of propidium iodide from the peripheral anionic site of hAChE. Hybrids 6g and 10f also elicited favorable permeation across the blood-brain barrier and were devoid of neurotoxic liability toward SH-SY5Y neuroblastoma cells. Both leads remarkably disassembled Aβ aggregation in thioflavin T-based selfand AChE-induced experiments. Compounds 6g and 10f ameliorated scopolamine-induced cognitive dysfunctions in the Ymaze test. The ex vivo studies of rat brain homogenates established the reduced AChE levels and antioxidant activity of both compounds. Compound 6g also elicited noteworthy improvement in Aβ-induced cognitive dysfunctions in the Morris water maze test with downregulation in the expression of Aβ and BACE-1 proteins corroborated by Western blot and immunohistochemical analysis. The pharmacokinetic study showed excellent oral absorption characteristics of compound 6g. The in silico molecular docking and dynamics simulation studies of lead compounds affirmed their consensual binding interactions with PAS-AChE and aspartate dyad of BACE-1.

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“…The BBB permeability of test compounds was predicted by parallel artificial membrane permeation assay (PAMPA) reported by Di et al (35,42). For detailed protocol of PAMPA assay, refer to Supporting Information-Experimental section.…”

Section: -(5-(4-hydroxy-3-methoxystyryl)-134oxadiazol-2-yl)-26-dimentioning

confidence: 99%

Design and Development of Multifunctional Hybrids of Ferulic Acid and 1,3,4-Oxadiazoles for the Treatment of Alzheimer’s Disease

Tripathi¹,

Choubey²,

Seth³

et al. 2020

CTBP

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Design, synthesis, evaluation and molecular modeling studies of some novel N-substituted piperidine-3-carboxylic acid derivatives as potential anticonvulsants

Cited by 33 publications

References 49 publications

Structural Modification, In Vitro, In Vivo, Ex Vivo, and In Silico Exploration of Pyrimidine and Pyrrolidine Cores for Targeting Enzymes Associated with Neuroinflammation and Cholinergic Deficit in Alzheimer’s Disease

Structural Modification, In Vitro, In Vivo, Ex Vivo, and In Silico Exploration of Pyrimidine and Pyrrolidine Cores for Targeting Enzymes Associated with Neuroinflammation and Cholinergic Deficit in Alzheimer’s Disease

Novel Molecular Hybrids of N-Benzylpiperidine and 1,3,4-Oxadiazole as Multitargeted Therapeutics to Treat Alzheimer’s Disease

Design and Development of Multifunctional Hybrids of Ferulic Acid and 1,3,4-Oxadiazoles for the Treatment of Alzheimer’s Disease

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