This study presents the first synthesis of seven novel coumarin annulates, each composed of a linear pattern of four heteroatoms (one sulfur and three oxygen atoms). The synthetic process was confirmed using spectroscopic techniques such as 1H-NMR, 13C-NMR, and FTIR. The synthesized annulates were evaluated for their biomedical potential, including antioxidant stress, anti-inflammatory, antidiabetic, anticancer, and antimicrobial activities. Additionally, their biosafety against nontumor cells and commensal bacterial strains was assessed. Computer-aided programs were used to explore their toxicity and pharmacokinetic profiles. Key findings include strong anti-inflammatory and antifungal properties of HC1, significant antioxidative stress and anticancer potential of HC2, and strong antibacterial activity of HC3. HC6 and HC7 showed promising antidiabetic properties, while all annulates exhibited favorable toxicity and oral bioavailability. These results suggest that the synthesized annulates have the potential to be useful frameworks for developing new drugs with broad bioactivity.This study presents the first synthesis of seven novel coumarin annulates, each composed of a linear pattern of four heteroatoms (one sulfur and three oxygen atoms). The synthetic process was confirmed using spectroscopic techniques such as 1H-NMR, 13C-NMR, and FTIR. The synthesized annulates were evaluated for their biomedical potential, including antioxidant stress, anti-inflammatory, antidiabetic, anticancer, and antimicrobial activities. Additionally, their biosafety against nontumor cells and commensal bacterial strains was assessed. Computer-aided programs were used to explore their toxicity and pharmacokinetic profiles. Key findings include strong anti-inflammatory and antifungal properties of HC1, significant antioxidative stress and anticancer potential of HC2, and strong antibacterial activity of HC3. HC6 and HC7 showed promising antidiabetic properties, while all annulates exhibited favorable toxicity and oral bioavailability. These results suggest that the synthesized annulates have the potential to be useful frameworks for developing new drugs with broad bioactivity.