Synthesis and anticonvulsant activity of novel 2,6-diketopiperazine derivatives. Part 2: Perhydropyrido[1,2-a]pyrazines

Dawidowski, Maciej; Herold, Franciszek; Chodkowski, Andrzej; Kleps, Jerzy

doi:10.1016/j.ejmech.2011.11.032

Cited by 19 publications

(13 citation statements)

References 11 publications

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“…According to our previous reports on bicyclic 2,6-DKP derivatives, the ( R , S ) isomers were completely devoid of any in vivo pharmacological activity (Dawidowski et al , 2011, 2012a). In contrast, the monocyclic derivatives (3 R ,5 S )-3a and (3 R ,5 S )-3e , displayed a weak, yet noticeable activity in the MES test (1/1 and 1/4 at 300 mg, respectively, at 0.5 h).…”

Section: Resultsmentioning

confidence: 89%

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Multicomponent synthesis and anticonvulsant activity of monocyclic 2,6-diketopiperazine derivatives

Dawidowski

Turło

2013

Med Chem Res

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In this study, a series of diastereomerically pure monocyclic 2,6-diketopiperazine (2,6-DKP) derivatives were synthesized. The key synthetic step involved a multicomponent Ugi five-center, four-component reaction which was used to generate the convertible tert-butylamidoesters with both good yields and high diastereoselectivity toward the desired bioactive (S,S) absolute configuration. In subsequent steps, selective tertbutyl cleavage by use of BF3·CH3COOH and base-induced intramolecular cyclocondensation gave the final 2,6-DKP derivatives. The relative stereochemistry of the target molecules was confirmed by 1H NMR experiments. The compounds obtained were submitted to in vivo screening in animal models of epilepsy. Some of them displayed good activity in maximal electroshock seizure and 6 Hz tests.

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Section: Resultsmentioning

confidence: 89%

“…Recently, we have reported that chiral, bicyclic 2,6-diketopiperazines (2,6-DKPs) derived from cyclic amino acids display a broad anticonvulsant activity in various animal models of epilepsy (Dawidowski et al , 2011, 2012a). Among the newly developed agents, compound ADD408003 exhibited a broad spectrum of seizure-suppressing activity.…”

Section: Introductionmentioning

confidence: 99%

Multicomponent synthesis and anticonvulsant activity of monocyclic 2,6-diketopiperazine derivatives

Dawidowski

Turło

2013

Med Chem Res

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“…The anticonvulsant activity of the synthesized compounds ( 3a – j ) was determined using two animal models of seizure according to the standard protocols within the Antiepileptic Drug Development (ADD) Program at National Institute of Neurological Disorders and Stroke, National Institutes of Health, Rockville, USA which included maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) . Almost all clinically significant AEDs are protective in at least one of these two models . In addition to the initial anticonvulsant screen, acute neurotoxocity (NT) was evaluated in the rotarod test .…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Evaluation of 5‐(o‐Tolyl)‐1H‐tetrazole Derivatives as Potent Anticonvulsant Agents

Dong¹,

Wang²,

Wang

et al. 2017

Archiv der Pharmazie

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A series of 5-(o-tolyl)-1H-tetrazole derivatives were synthesized and evaluated for their anticonvulsant activities. 1-(2-Methylbenzyl)-5-(o-tolyl)-1H-tetrazole (3h) showed important anticonvulsant activity against the MES-induced seizures, as well as lower neurotoxicity with an ED value of 12.7 mg/kg and a TD value of over 500 mg/kg after intraperitoneal injection into mice, providing 3h with a high protective index (TD /ED ) of over 39.4. The achieved results prove that the distinctive compounds could be valuable as a model for future development, adaptation, and investigation to construct more active analogues.

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“…Epilepsy is a group of neurological disorders characterized by excessive abnormal bioelectrical functions of the brain leading to recurrent unprovoked seizures [ 1 , 2 ]. It affects about 1% of the global population with the majority of cases being in the developing countries [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Anticonvulsant Profiles of Certain New 6-Aryl-9-substituted-6,9-diazaspiro-[4.5]decane-8,10-diones and 1-Aryl-4-substituted-1,4-diazaspiro[5.5]undecane-3,5-diones

Aboul‐Enein

El‐Azzouny

Attia

et al. 2014

IJMS

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Synthesis and anticonvulsant potential of certain new 6-aryl-9-substituted-6,9-diazaspiro[4.5]decane-8,10-diones (6a–l) and 1-aryl-4-substituted-1,4-diazaspiro[5.5]undecane-3,5-diones (6m–x) are reported. The intermediates 1-[(aryl)(cyanomethyl)amino]cycloalkanecarboxamides (3a–f) were prepared via adopting Strecker synthesis on the proper cycloalkanone followed by partial hydrolysis of the obtained nitrile functionality and subsequent N-cyanomethylation. Compounds 3a–f were subjected to complete nitrile hydrolysis to give the respective carboxylic acid derivatives 4a–f which were cyclized under mild conditions to give the spiro compounds 5a–f. Ultimately, compounds 5a–f were alkylated or aralkylated to give the target compounds 6a–i and 6m–u. On the other hand, compounds 6j–l and 6v–x were synthesized from the intermediates 5a–f through alkylation, dehydration and finally tetrazole ring formation. Anticonvulsant screening of the target compounds 6a–x revealed that compound 6g showed an ED50 of 0.0043 mmol/kg in the scPTZ screen, being about 14 and 214 fold more potent than the reference drugs, Phenobarbital (ED50 = 0.06 mmol/kg) and Ethosuximide (ED50 = 0.92 mmol/kg), respectively. Compound 6e exhibited an ED50 of 0.019 mmol/kg, being about 1.8 fold more potent than that of the reference drug, Diphenylhydantoin (ED50 = 0.034 mmol/kg) in the MES screen. Interestingly, all the test compounds 6a–x did not show any minimal motor impairment at the maximum administered dose in the neurotoxicity screen.

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Synthesis and anticonvulsant activity of novel 2,6-diketopiperazine derivatives. Part 2: Perhydropyrido[1,2-a]pyrazines

Cited by 19 publications

References 11 publications

Multicomponent synthesis and anticonvulsant activity of monocyclic 2,6-diketopiperazine derivatives

Multicomponent synthesis and anticonvulsant activity of monocyclic 2,6-diketopiperazine derivatives

Synthesis and Evaluation of 5‐(o‐Tolyl)‐1H‐tetrazole Derivatives as Potent Anticonvulsant Agents

Anticonvulsant Profiles of Certain New 6-Aryl-9-substituted-6,9-diazaspiro-[4.5]decane-8,10-diones and 1-Aryl-4-substituted-1,4-diazaspiro[5.5]undecane-3,5-diones

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