Synthesis, characterization, and preliminary anticancer evaluation of a novel ۱,۲,۴-triazole-substituted caffeine derivative

Structural modification of caffeine with nitrogen-containing heterocycles has emerged as a promising strategy for developing novel anticancer agents. This study aimed to synthesize, characterize, and preliminarily evaluate the anticancer potential of a novel caffeine–triazole hybrid, ۱,۳,۷-trimethyl-۸-(۱H-۱,۲,۴-triazol-۱-yl)-۳,۷-dihydro-۱H-purine-۲,۶-dione (۸-(۱,۲,۴-triazolyl)caffeine). The compound was synthesized via nucleophilic substitution of ۸-chlorocaffeine with ۱,۲,۴-triazole and structurally characterized by UV–Vis, FT-IR, ¹H NMR, ¹³C NMR, and LC–MS analyses. Optimization of the reaction time afforded the target compound in a maximum yield of ۳۴.۱۱% after ۹ h. Preliminary anticancer potential was assessed using the Brine Shrimp Lethality Test (BSLT) and molecular docking against human epidermal growth factor receptor ۲ (HER-۲), estrogen receptor beta (ER-β), and progesterone receptor (PR). The synthesized derivative exhibited greater cytotoxicity than caffeine, as indicated by a lower LC۵۰ value in the BSLT assay. Molecular docking predicted stronger binding affinities than caffeine toward all investigated receptors and comparable interactions with the reference ligands against HER-۲ and PR. These findings suggest that incorporation of a ۱,۲,۴-triazole moiety into the caffeine scaffold improves its molecular interactions with breast cancer-related targets and provides a promising scaffold for further biological evaluation.

کلیدواژه ها:

Caffeine-derived ، Novel ۸-(۱-۲-۴-triazolyl)caffeine ، Preliminary anticancer ، In Silico