Eco-Friendly Ultrasonic Synthesis of 1,8-Naphthyridine Derivatives: Optimization, Antioxidant Activity, and Computational ADME Study

An efficient and environmentally friendly method was developed for the synthesis of novel 1,8-naphthyridine derivatives through a one-pot multicomponent reaction under ultrasonic irradiation. The reaction of quinoline-2-amine, malononitrile, and various substituted aldehydes was carried out in water using morpholine as a catalyst, affording the desired 1,8-naphthyridine-3-carbonitrile derivatives in high yields within a short reaction time. The ultrasound-assisted protocol significantly improved reaction efficiency compared with conventional methods by reducing reaction time and increasing product yield under mild conditions. The synthesized compounds were characterized by FT-IR, 1H NMR, 13C NMR, and mass spectrometry, confirming their molecular structures. The antioxidant potential of the synthesized derivatives was evaluated using the DPPH free radical scavenging assay. Among the series, compounds 4g and 4j exhibited the most promising antioxidant activity with lower IC50 values, indicating strong radical-scavenging ability. Furthermore, in-silico ADME and drug-likeness analyses using the SwissADME platform revealed that most compounds possess favorable physicochemical properties, good gastrointestinal absorption, and compliance with drug-likeness rules. Overall, this study presents a rapid and green synthetic strategy for generating biologically relevant 1,8-naphthyridine derivatives with promising antioxidant properties. The developed methodology supports Sustainable Development Goals (SDG 3: Good Health and Well-being and SDG 12: Responsible Consumption and Production) by promoting environmentally responsible chemical synthesis and potential therapeutic discovery.