One-Pot Microwave-Assisted Synthesis of Chlorinated Benzylamine-Substituted Pyrazine Derivatives and In Silico Studies of Their Potential as EGFR and HER۲ Inhibitors

Pyrazine is widely used in pharmaceuticals, and benzylamine offers advantages due to its reactive amine group, while the chloro-substituent may enhance its metabolic stability. This suggests that the structural modification of pyrazines using chlorinated benzylamine may provide novel molecules with enhanced biological activity; however, such modifications have not been extensively pursued. This study aims to synthesize chlorinated benzylamine-substituted pyrazine derivatives, obtain an effective synthetic method, and determine their potential as EGFR and HER۲ inhibitors. Synthesis was carried out using three methods, namely microwave-assisted synthesis (MAS), ultrasound-assisted synthesis (UAS), and conventional methods. Three benzylamine-substituted pyrazine derivatives, namely ۳-amino-N-(۳-chlorobenzyl)pyrazine-۲-carboxamide (۱), ۳-amino-N-(۴-chlorobenzyl)pyrazine-۲-carboxamide (۲), and ۳-amino-N-(۲,۴-dichlorobenzyl)pyrazine-۲-carboxamide (۳), have been successfully synthesized. The structures of compounds ۱-۳ have been determined comprehensively based on FT-IR, ۱H- NMR, ۱۳C-NMR, HMBC, HSQC, and HRMS spectra. MAS proved to be superior, performing the synthesis in a much faster time (۳۰ min), with higher yields (۷۸-۹۳%) compared to UAS (۶۱-۶۹%) and conventional methods (۵۸-۶۵%). Compound ۱ is predicted to be more favorable as an EGFR inhibitor, while compound ۳ is more favorable as an HER۲ inhibitor. Predicted pharmacokinetics, toxicity, and drug-likeness of compounds ۱-۳ provide a good initial safety prediction, but experimental toxicology is necessary to confirm the safety issues. These three compounds are recommended for further in vitro and in vivo studies as EGFR and HER۲ inhibitors.

کلیدواژه ها:

pyrazine ، chlorinated benzylamine ، microwave-assisted syntesis ، Molecular docking