Novel 1,3-dioxolane–coumarin hybrids: From synthesis to pharmacological In Vitro-In Silico profiling

In this study, we report the design, synthesis, and comprehensive biological evaluation of a novel series of linear 1,3-dioxolane–coumarin hybrids (DCH1–DCH7) as promising multi-target therapeutic agents. The synthesis involved an optimized multi-step approach beginning with a Pechmann condensation followed by selective esterification reactions, yielding high-purity compounds confirmed via FTIR, 1H-NMR, and 13C-NMR analyses. The hybrids were systematically screened for their antioxidant, anticancer, anti-inflammatory, antidiabetic, and antimicrobial activities. In addition, their biocompatibility was assessed using non-cancerous human cell lines and commensal bacterial strains. Among the synthesized hybrids, DCH4 exhibited remarkable antioxidant and anticancer properties, while DCH1 showed superior anti-inflammatory and antifungal activity. DCH2 demonstrated potent antidiabetic and anti-anaerobic bacterial efficacy, and DCH5 emerged as the most active against aerobic gram-negative bacteria. These bioactivities were closely linked to specific structural modifications, as revealed through structure–activity relationship analyses. In silico evaluations using ProTox-II, PreADME, and SwissADME tools predicted favorable drug-likeness, low toxicity, high oral bioavailability, and acceptable pharmacokinetic profiles, further supporting their therapeutic relevance. Importantly, all hybrids displayed minimal cytotoxic effects on non-cancerous cells and exhibited selective antimicrobial actions, sparing beneficial gut microbiota. This highlights their potential as safer alternatives to conventional therapies. The introduction of the 1,3-dioxolane moiety into the coumarin scaffold contributed significantly to the observed bioactivities, suggesting this hybrid framework as a versatile platform for future drug development. Overall, our findings establish these 1,3-dioxolane–coumarin hybrids as promising multifunctional drug candidates with broad-spectrum pharmacological potential and a strong safety profile, warranting further investigation and development.