Environmentally Friendly Synthesis of Coumarin–Pyrazolo[1,5-a]pyrimidine Hybrids with Potent Antibacterial and Antibiofilm Activities

Objective: This study aimed to synthesize a series of coumarin–pyrazolo[1,5-a]pyrimidine hybrid compounds and evaluate their potential antibacterial and antibiofilm activities. Methods: In our synthetic approach, a mixture of 3-acetylcoumarin (I) and N,N-dimethylformamide dimethyl acetal (DMF-DMA) was refluxed in toluene to afford the enaminone intermediate (II). Subsequent condensation with 3-aminopyrazoles in the presence of potassium hydrogen sulfate (KHSO₄) yielded a series of 7-(2-oxo-2H-chromen-3-yl)pyrazolo[1,5-a]pyrimidine derivatives. The structures of the synthesized compounds were confirmed using spectroscopic and analytical techniques, including FT-IR, ¹H, ¹³C NMR, and high-resolution mass spectrometry (HRMS). Antibacterial and antibiofilm activities were evaluated against Staphylococcus epidermidis ATCC 35984 and Pseudomonas aeruginosa using MIC, MIC₅₀ assays, and biofilm formation inhibition studies. Results and Discussion: The synthesized coumarin–pyrazolo[1,5-a]pyrimidine (CPP) hybrids (IVa–IVj) were obtained in high yields (74–92%) within short reaction times (9–18 min). These compounds exhibited significant anti-adhesion and antibiofilm activities against both S. epidermidis and P. aeruginosa. All compounds were tested for their ability to inhibit bacterial cell adhesion to polystyrene surfaces. Conclusions: Hybrids (IVd) and (IVe) demonstrated outstanding and consistent antibiofilm activity against strong biofilm-forming strains, S. epidermidis ATCC 35984 and P. aeruginosa, indicating broad-spectrum efficacy at low concentrations.