Heterocyclic Coumarin Derivatives as Multifunctional Biosafe Candidates: Bridging Synthetic Chemistry with In Vitro and In Silico Evaluations

Objective: This research presents the synthesis of fourteen novel coumarin derivatives, each fused with one of two distinct five-membered heterocycles, with the aim that these easily accessible coumarin frameworks will have a wide range of modifiable biomedical applications. Methods: The molecular structures of the synthesized derivatives were confirmed using spectroscopic methods, namely 1H, 13C NMR, and FT-IR. The biomedical potential of these derivatives as antiproliferative, antioxidant, antidiabetic, anti-inflammatory, and antimicrobial agents was evaluated in vitro. Additionally, their biosafety toward non-infective bacterial strains and non-malignant cells was assessed. To investigate the pharmacokinetic and toxicological profiles of these derivatives, computational tools were employed. Results and Discussion: The authors identified the following key outcomes from the collected data. The type of fused heterocycle significantly influences the biomedical potential of the investigated derivatives. Compound A1 showed considerable anti-inflammatory activity via the lipoxygenase-dependent pathway and outperformed Nystatin in terms of antifungal potential. Compounds A2, A3, B2, and B3 exhibited great potential as antidiabetic candidates due to their potent glucosidase and amylase inhibitory properties. Compounds A4 and B4 demonstrated strong antioxidant, antiproliferative, and biosafety profiles. In terms of antibacterial activity, A5 and B5 were comparable to Ciprofloxacin against all the aerobic bacterial strains tested. Moreover, the biosafety profiles against non-infective bacterial strains were favorable for all the synthesized derivatives, particularly for this pair. Lastly, the synthesized derivatives exhibited favorable profiles regarding oral bioavailability and toxicity. Conclusions: These derivatives may serve as valuable building blocks for the future development of novel pharmaceuticals with a broad range of bioactivities.