Synthesis and development of new 2-substituted 1-[3-(4-arylpiperazin-1-yl)propyl]-pyrrolidin-2-one derivatives with antiarrhythmic, hypotensive, and alpha-adrenolytic activity |
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Authors: | Malawska Barbara Kulig Katarzyna Gippert Annika Filipek Barbara Sapa Jacek Maciag Dorota |
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Affiliation: | Department of Physicochemical Drug Analysis, Jagiellonian University, Medical College, Kraków, Poland. mfmalaws@cyf-kr.edu.pl |
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Abstract: | A series of new 1-3-(4-arylpiperazinyl-1-yl)-2-(N-alkylcarbamoyloxy)propyl]-pyrrolidin-2-one derivatives (4a-12a) were synthesised and tested for their electrocardiographic, antiarrhythmic and antihypertensive activity, as well as for the alpha1- and alpha2-adrenoceptor binding affinities. Of the newly synthesised derivatives, 1-{2-(N-2-methylethylcarbamoiloxy)-3-4-(2-methoxyphenyl)piperazin-1-yl)]propyl}pyrrolidin-2-one dihydrochloride (10a) was the most active in prophylactic antiarrhythmic tests, its ED50 value equalling 2.7 mg kg(-1), and the therapeutic index being 75.2; moreover, compound 10a was also found to possess hypotensive activity. A preliminary molecular modelling study suggested that the selected alpha1-AR antagonist distances and angles between pharmacophoric features, estimated for the tested compounds, were in good agreement with the parameters evaluated for ligands. |
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Keywords: | N-(4-Arylpiperazin-1-yl)propylpyrrolidin-2-one derivatives Antiarrhythmic Hypotensive α-Adrenoceptor blocking activity Molecular modelling |
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