Synthesis of Novel Artesunate Derivatives by Multicomponent Reactions
摘要
Objective: This study aimed to synthesize new artesunate-based derivatives via multicomponent reactions, including Ugi, Mannich, and Cu(I)-catalyzed azide-alkyne cycloaddition (click chemistry). Additionally, the antiviral activity of these derivatives against the SARS-CoV-2 pseudovirus was assessed. Methods: The artesunate derivatives were synthesized using Ugi reactions to form α-acetoamidocarboxamides, Mannich reactions to generate aminomethyl derivatives, and click chemistry to produce triazole-linked conjugates with sugar moieties. The antiviral activity of the resulting sugar-triazole-artesunate hybrids was evaluated in vitro using BHK-21-hACE2 cells infected with the SARS-CoV-2 pseudovirus. The half-maximal inhibitory concentration (IC50) was determined through a dose-response assay. Results and Discussion: The synthesis resulted in high yields of artesunate derivatives with diverse structures. Among them, compound VIII, a sugar-triazole-artesunate hybrid, displayed promising antiviral activity against the SARS-CoV-2 pseudovirus with an IC50 of 1.5 µM, approximately twice as potent as the reference drug amodiaquine. Cytotoxicity analysis further confirmed the selectivity of this compound, yielding a selectivity index (SI) of 28.28, suggesting a favorable therapeutic profile. Conclusions: The successful synthesis of novel artesunate derivatives via multicomponent reactions was achieved, with the sugar-triazole conjugate demonstrating significant antiviral activity against the SARS-CoV-2 pseudovirus. These findings highlight the potential of such conjugates as candidates for further development in antiviral therapies.