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Molecules 2014, 19(10), 15955-15981; doi:10.3390/molecules191015955

Synthesis of New Perhydropyrrolo[1,2-a]pyrazine Derivatives and Their Evaluation in Animal Models of Epilepsy

1
Department of Drug Technology and Pharmaceutical Biotechnology, Medical University of Warsaw, Banacha 1 Str., 02-097 Warszawa, Poland
2
Faculty of Pharmacy, Medical University of Warsaw, Banacha 1 Str., 02-097 Warszawa, Poland
*
Author to whom correspondence should be addressed.
Received: 20 August 2014 / Revised: 24 September 2014 / Accepted: 26 September 2014 / Published: 7 October 2014
(This article belongs to the Section Medicinal Chemistry)
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Abstract

A series of novel stereochemically pure derivatives of the investigative broad-spectrum anticonvulsant ADD408003 was designed and synthesized. Five-center four-component (U-5C-4CR) and four-center three-component (U-4C-3CR) variants of Ugi reaction were used in the key step of the synthetic pathways. The compounds obtained were evaluated for the anticonvulsant activitiy in the maximal electroshock seizure (MES), subcutaneous Metrazole (scMET) and minimal clonic seizure (6 Hz) animal models of epilepsy. The efficacies of most derivatives in the 6 Hz model of pharmacoresistant partial seizures were markedly higher than in the ‘classical’ MES and scMET models. The most active compounds, (4R,8aR)-3a, and (4S,8aS)-6 displayed median effective doses (ED50) of 47.90 and 126.19 mg/kg, respectively, for the 6 Hz test. View Full-Text
Keywords: 2,6-diketopiperazine; pyrrolo[1,2-a]pyrazine; multicomponent reaction; Ugi reaction; U-5C-4CR; U-4C-3CR; anticonvulsant agent; antiseizure agent; antiepileptic agent 2,6-diketopiperazine; pyrrolo[1,2-a]pyrazine; multicomponent reaction; Ugi reaction; U-5C-4CR; U-4C-3CR; anticonvulsant agent; antiseizure agent; antiepileptic agent
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Dawidowski, M.; Lewandowski, W.; Turło, J. Synthesis of New Perhydropyrrolo[1,2-a]pyrazine Derivatives and Their Evaluation in Animal Models of Epilepsy. Molecules 2014, 19, 15955-15981.

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