Synthesis of Dioxane-fused Coumarins as a new class of biosafe multifunctional therapeutic candidates: A journey from In Vitro to In Silico prediction

This study presents for the first time the novel synthesis and in vitro-in silico bio-evaluation of seven coumarin derivatives linearly conjugated with a 1,4-dioxane ring. The primary goal was to develop accessible and modifiable coumarin-based scaffolds with a broad spectrum of biological activities. The structural identities of the synthesized compounds were confirmed using various spectroscopic techniques, including 1H-NMR, 13C-NMR, and FTIR analyses. The biological potential of the synthesized fused structures was systematically evaluated through a series of in vitro assays. Notably, DFC4 emerged as a promising candidate with strong antioxidative stress activity. In terms of antidiabetic potential, DFC2 demonstrated significant inhibition of both α-glucosidase and α-amylase enzymes, suggesting its usefulness in managing hyperglycemia. DFC5 exhibited potent antibacterial effects, comparable to those of ciprofloxacin, against all tested aerobic bacterial strains. In addition, DFC1 showed superior antifungal activity, outperforming nystatin. The same fused structure also displayed noteworthy anti-inflammatory properties, likely through a cyclooxygenase-dependent mechanism. Regarding anticancer properties, DFC4 again stood out by exhibiting effective cytotoxicity toward cancer cells while maintaining biosafety toward non-carcinogenic cells. All synthesized fused structures, especially DFC5, demonstrated favorable biosafety profiles when tested against commensal bacterial strains. To complement the in vitro findings, computational tools were used to predict the toxicity and pharmacokinetic profiles of the structures under evaluation. The results indicated that the synthesized fused structures possess desirable biosafety thresholds and oral bioavailability characteristics. Collectively, these findings suggest that the newly synthesized fused structures hold significant potential as multifunctional therapeutic agents for future drug development.