Sustainable synthesis of Schiff base derivatives via an ionic liquid and a microwave-assisted approach: structural, biological, and computational evaluation†

A sustainable and efficient microwave-assisted strategy was developed for the synthesis of novel 4-amino-pyrrolo [2,3-d]pyrimidine-based Schiff base derivatives (APR1a–d), utilizing the ionic liquid 1-hexyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([HMIM][TFSI]) as both catalyst and solvent. This green protocol afforded high yields (82–94%) under mild conditions with excellent reusability of the ionic liquid. Structural confirmation was achieved via FT-IR, ¹H and ¹³C NMR, and mass spectrometry. The antimicrobial potential of the synthesized compounds was assessed against a panel of Gram-positive and Gram-negative bacteria, as well as pathogenic yeast strains. Among them, APR1d exhibited the most potent antibacterial activity (up to 28 mm inhibition against B. subtilis) and broad-spectrum antifungal efficacy (up to 19 mm inhibition against C. albicans and S. cerevisiae). Cytotoxicity analysis via brine shrimp lethality assay indicated low toxicity, with LC₅₀ values of 3.50 × 10⁻⁴ M (APR1b) and 8.50 × 10⁻⁴ M (APR1c). Density Functional Theory (DFT) analysis revealed that APR1d possessed the smallest HOMO–LUMO gap (0.0679 eV) and highest electrophilicity index (0.4288 eV), supporting its high reactivity. Molecular electrostatic potential maps and global reactivity descriptors (μ, η, S, ω, χ) further elucidated the electronic distribution and interaction potential. Molecular docking and MM/PBSA analyses confirmed APR1d's strong and stable binding to key microbial target proteins, surpassing standard drugs in binding affinity. These results underscore APR1d as a promising lead candidate with significant therapeutic potential, while highlighting the synergy of green chemistry, computational modeling, and biological validation in modern drug discovery.