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DOI: 10.1055/a-2771-1646
Efficient Synthesis and Characterization of Lidocaine Analogue N-Ethyl-N-((8-methylquinazolin-2-yl)methyl)ethanamine
Authors
This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. RS-2023-00220894). This study was supported by a grant from Korea University.
Abstract
N-Ethyl-N-((8-methylquinazolin-2-yl)methyl)ethanamine, a novel quinazoline-based lidocaine analogue, was efficiently synthesized on a 10-g scale via a seven-step process with 44.3% overall yield. Key synthetic transformations achieved excellent yields (80–92%): LiAlH4 reduction, diethylamine substitution, MnO2 oxidation, and intramolecular cyclization. Comprehensive in vitro evaluation revealed favorable safety and pharmacological profiles. Toxicity assays across HEK293, PC12, and H9c2 cell lines demonstrated IC20 values of 5.8–10.8 μM with appropriate safety margins. Caco-2 permeability studies showed high membrane penetration (Papp: 1.35 × 10–8 cm/s, efflux ratio: 0.89), comparable to lidocaine. Critically, it exhibited 2.64-fold enhanced potency toward Nav1.5 sodium channels in inactivated state (IC50 = 8.86 ± 1.2 μM vs. lidocaine 23.40 ± 2.6 μM) while maintaining state-dependent blocking characteristics. Metabolic stability was superior to lidocaine, with hepatic half-life of 23.26 minutes (26% longer). These results, combining enhanced pharmacological potency, acceptable toxicity, superior metabolic stability, and reliable synthesis, position N-ethyl-N-((8-methylquinazolin-2-yl)methyl)ethanamine as a promising next-generation local anesthetic candidate warranting further clinical development.
Key words
lidocaine analogue - quinazoline - local anesthetic - sodium channel antagonist - patch-clamp electrophysiology - in vitro toxicology - ADMESupporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/a-2771-1646.
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Publication History
Received: 12 November 2025
Accepted after revision: 10 December 2025
Article published online:
22 January 2026
© 2026. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by/4.0/)
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