Synthesis and Evaluation of Voltage-Gated Sodium Channel Blocking Pyrroline Derivatives Endowed with Both Antiarrhythmic and Antioxidant Activities.

Abstract

Under the hypothesis that cardioprotective agents might benefit from synergism between antiarrhythmic activity and antioxidant properties, a small series of mexiletine analogues were coupled with the 2,2,5,5-tetramethylpyrroline moiety, known for its antioxidant effect, in order to obtain dual-acting drugs potentially useful in the protection of the heart against post-ischemic reperfusion injury. The pyrroline derivatives reported herein were found to be more potent as antiarrhythmic agents than mexiletine and displayed antioxidant activity. The most interesting tetramethylpyrroline congener, a tert-butyl-substituted analogue, was at least 100 times more active as an antiarrhythmic than mexiletine.

• Authors: Alessia Carocci, Mariagrazia Roselli, Roberta Budriesi, Matteo Micucci, Jean-François Desaphy, Concetta Altamura, Maria Maddalena Cavalluzzi, Maddalena Toma, Giovanna Ilaria Passeri, Gualtiero Milani, Angelo Lovece, Alessia Catalano, Claudio Bruno, Annalisa De Palma, Filomena Corbo, Carlo Franchini, Solomon Habtemariam, Giovanni Lentini
• Journal: ChemMedChem (ChemMedChem) Vol. 16 Issue 3 Pg. 578-588 (02 04 2021) ISSN: 1860-7187 [Electronic] Germany
• PMID: 33015979 (Publication Type: Journal Article)
• Copyright: © 2020 Wiley-VCH GmbH.

Chemical References

• Anti-Arrhythmia Agents
• Antioxidants
• Fluoresceins
• Pyrroles
• Voltage-Gated Sodium Channel Blockers
• Voltage-Gated Sodium Channels
• 2',7'-dichlorodihydrofluorescein
• pyrroline

Topics

• Animals
• Anti-Arrhythmia Agents (chemical synthesis, chemistry, pharmacology)
• Antioxidants (chemical synthesis, chemistry, pharmacology)
• Density Functional Theory
• Fluoresceins (metabolism)
• Guinea Pigs
• Humans
• Molecular Structure
• Pyrroles (chemical synthesis, chemistry, pharmacology)
• Reperfusion Injury (drug therapy, metabolism)
• Tumor Cells, Cultured
• Voltage-Gated Sodium Channel Blockers (chemical synthesis, chemistry, pharmacology)
• Voltage-Gated Sodium Channels (metabolism)