Green ultrasound assisted synthesis of theophylline triazole acetamide hybrids and their antimicrobial and computational evaluation
- 1Department Of Chemistry, Saurashtra University
- 2Microbiology Department, Harivandana College
- 3Department of Bioscience, Saurashtra University
Abstract
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, 1H NMR, 13C 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. Graphical Abstract This diagram outlines the synthesis and evaluation process of theophylline-1,2,3-triazole derivatives labeled 8a to 8j. The process begins with a chemical reaction involving specific starting materials and reagents—DMF, tert-butanol, water, copper sulfate pentahydrate, and sodium ascorbate—undergoing a sonochemical reaction. The resulting derivatives are then subjected to four parallel analyses: antimicrobial screening against specified Gram-positive bacteria (Staphylococcus aureus, Bacillus cereus, Corynebacterium rubrum) and Gram-negative bacteria (Pseudomonas aeruginosa, Salmonella typhimurium, Escherichia coli); molecular docking studies using protein data bank identifiers 5L3J for Escherichia coli and 3G75 for Staphylococcus aureus; ADME profiling assessing absorption, distribution, metabolism, and excretion properties; and density functional theory analysis showing molecular orbital diagrams. The antimicrobial screening leads to structure-activity relationship analysis.
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BibTeX
@article{khoyanee2026green,
title = {{Green ultrasound assisted synthesis of theophylline triazole acetamide hybrids and their antimicrobial and computational evaluation}},
author = {Anjalee Khoyanee and Priyank Shah and Amita Vyas and Kalpna Rakholiya and Mital Kaneria and Ranjan Khunt},
journal = {Discover Chemistry},
year = {2026},
month = oct,
doi = {10.1007/s44371-026-01039-z},
url = {https://doi.org/10.1007/s44371-026-01039-z},
note = {CC BY},
}
RIS
TY - JOUR
TI - Green ultrasound assisted synthesis of theophylline triazole acetamide hybrids and their antimicrobial and computational evaluation
AU - Anjalee Khoyanee
AU - Priyank Shah
AU - Amita Vyas
AU - Kalpna Rakholiya
AU - Mital Kaneria
AU - Ranjan Khunt
PY - 2026
DA - 2026/10/25
JO - Discover Chemistry
DO - 10.1007/s44371-026-01039-z
UR - https://doi.org/10.1007/s44371-026-01039-z
AB - 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, 1H NMR, 13C 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. Graphical Abstract This diagram outlines the synthesis and evaluation process of theophylline-1,2,3-triazole derivatives labeled 8a to 8j. The process begins with a chemical reaction involving specific starting materials and reagents—DMF, tert-butanol, water, copper sulfate pentahydrate, and sodium ascorbate—undergoing a sonochemical reaction. The resulting derivatives are then subjected to four parallel analyses: antimicrobial screening against specified Gram-positive bacteria (Staphylococcus aureus, Bacillus cereus, Corynebacterium rubrum) and Gram-negative bacteria (Pseudomonas aeruginosa, Salmonella typhimurium, Escherichia coli); molecular docking studies using protein data bank identifiers 5L3J for Escherichia coli and 3G75 for Staphylococcus aureus; ADME profiling assessing absorption, distribution, metabolism, and excretion properties; and density functional theory analysis showing molecular orbital diagrams. The antimicrobial screening leads to structure-activity relationship analysis.
SN - 3005-1193
ER -