Green ultrasound assisted synthesis of theophylline triazole acetamide hybrids and their antimicrobial and computational evaluation

The critical escalation of multidrug-resistant pathogens underscores an urgent need for structurally diverse, targeted therapeutic compounds. A series of novel theophylline-1,2,3-triazole-acetamide hybrids (LS-1 to LS-10) was efficiently synthesized via an ultrasound-assisted Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) strategy under environmentally benign conditions. The sonochemical protocol employed a DMF: t -BuOH: H₂O (1:1:1) solvent system and afforded the desired hybrids in excellent yields (90–96%) within 55 min, demonstrating significant advantages over conventional thermal methods in terms of reaction time, atom economy (89.8%) and reduced waste generation (E-factor = 0.335). Structural elucidation of all synthesized derivatives was comprehensively accomplished using FT-IR, 1 H NMR, 13 C NMR and mass spectrometric analyses. The antimicrobial potential of the synthesized compounds was evaluated against representative Gram-positive ( Staphylococcus aureus , Bacillus cereus , Corynebacterium rubrum ) and Gram-negative ( Pseudomonas aeruginosa , Salmonella typhimurium , Escherichia coli ) bacterial strains. Among the tested derivatives, halogen-substituted analogues LS-5, LS-6, LS-9 and LS-10 exhibited the most significant antibacterial activity, with inhibition zones reaching up to 32.5 mm and minimum inhibitory concentration (MIC) values as low as 46.9 µg/mL against Staphylococcus aureus and Pseudomonas aeruginosa . Structure–activity relationship analysis revealed that halogen substituents markedly enhanced antibacterial efficacy. To rationalize the observed biological activity, molecular docking studies were performed against bacterial DNA gyrase B targets (PDB IDs: 3G75 and 5L3J). Compounds LS-4 and LS-6 demonstrated the most favourable binding affinities (-9.0 and − 8.2 kcal/mol, respectively), surpassing or comparable to the reference ligand novobiocin through strong hydrogen-bonding and hydrophobic interactions within the ATP-binding pocket. Furthermore, ADME profiling indicated favourable drug-likeness, oral bioavailability and non-mutagenic behaviour, while DFT investigations revealed suitable electronic stability and reactivity. Collectively, these findings establish the synthesized theophylline-triazole hybrids as promising lead candidates for future antimicrobial drug development.