Current organic synthesis · 2026
Novel Azo-Oxazine-Tetrazole Hybrids Conjugated with TEMPO-oxidized Cellulose Nanocrystals: Synthesis, Antibacterial Evaluation, and Molecular Docking Against Drug-resistant S. aureus.
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Al-Mosawy Manar Ghyath Abd-Almutalib, Ghafil Rajaa Abdulameer, Shakoor Bushra, Afzal Kinza, Shafiq Nusrat, Naser N A
Аннотация
OBJECTIVE: The present investigation sought to conceptualize and fabricate a novel series of azo-oxazine-tetrazole hybrids (C1-C3) and to assess their prospective utility as antibacterial agents by integrating them into pH-responsive nanocomposites derived from TEMPO-oxidized Cellulose Nanocrystals (CNCs). The primary aim was to establish a controlled drug delivery system that demonstrates efficacy against Methicillin-Resistant Staphylococcus aureus (MRSA).
METHODS: The synthesis of azo-oxazine-tetrazole compounds was conducted through a series of multi-step chemical reactions, followed by their conjugation with TEMPO-oxidized CNCs. Structural validation was performed using Fourier-transform infrared (FT-IR) spectroscopy, and surface morphology was characterized by Scanning Electron Microscopy (SEM). Antibacterial activity was assessed employing the disc diffusion method, whereas molecular docking studies against the bacterial 6LXH protein elucidated binding affinities. Additionally, drug loading, release kinetics under variable pH conditions (5.5 and 7.4), and ADME (absorption, distribution, metabolism, excretion) characteristics were examined utilizing SwissADME computational tools.
RESULTS: FT-IR spectroscopy corroborated the successful synthesis of the hybrids and their conjugation to CNCs. SEM analysis illustrated uniform CNC fibrils with an average diameter measuring 15 ± 3 nm. The drug-loading efficiencies ranged from 79% to 86%. Among the evaluated compounds, C2 demonstrated the most pronounced antibacterial activity against MRSA, with an inhibition zone of 28 mm at 300 μg/mL. Molecular docking analyses indicated a significant binding affinity for C2, reflected in a MolDock score of -141.428. The drug release exhibited pH sensitivity, achieving 92% release at pH 5.5 and 68% at pH 7.4. Compounds C2 and C3 displayed favorable drug-likeness and low gastrointestinal absorption, coupled with minimal penetration across the blood-brain barrier.
DISCUSSION: This investigation demonstrates the successful formulation of pH-sensitive antibacterial nanocomposites with enhanced drug-delivery properties. The superior performance of C2 can be ascribed to its robust molecular interactions with bacterial proteins and its effective release in acidic environments, which are typically encountered at infection sites. Such findings underscore the hybrid's potential as a targeted therapeutic approach for combating drug-resistant infections.
CONCLUSION: The synthesized azo-oxazine-tetrazole-CNC nanocomposites, particularly C2, exhibit promising antibacterial efficacy, pH-responsive drug release profiles, and advantageous pharmacokinetic properties. These results substantiate their potential for application in the design of nextgeneration nanocarrier systems to address resistant bacterial infections.
METHODS: The synthesis of azo-oxazine-tetrazole compounds was conducted through a series of multi-step chemical reactions, followed by their conjugation with TEMPO-oxidized CNCs. Structural validation was performed using Fourier-transform infrared (FT-IR) spectroscopy, and surface morphology was characterized by Scanning Electron Microscopy (SEM). Antibacterial activity was assessed employing the disc diffusion method, whereas molecular docking studies against the bacterial 6LXH protein elucidated binding affinities. Additionally, drug loading, release kinetics under variable pH conditions (5.5 and 7.4), and ADME (absorption, distribution, metabolism, excretion) characteristics were examined utilizing SwissADME computational tools.
RESULTS: FT-IR spectroscopy corroborated the successful synthesis of the hybrids and their conjugation to CNCs. SEM analysis illustrated uniform CNC fibrils with an average diameter measuring 15 ± 3 nm. The drug-loading efficiencies ranged from 79% to 86%. Among the evaluated compounds, C2 demonstrated the most pronounced antibacterial activity against MRSA, with an inhibition zone of 28 mm at 300 μg/mL. Molecular docking analyses indicated a significant binding affinity for C2, reflected in a MolDock score of -141.428. The drug release exhibited pH sensitivity, achieving 92% release at pH 5.5 and 68% at pH 7.4. Compounds C2 and C3 displayed favorable drug-likeness and low gastrointestinal absorption, coupled with minimal penetration across the blood-brain barrier.
DISCUSSION: This investigation demonstrates the successful formulation of pH-sensitive antibacterial nanocomposites with enhanced drug-delivery properties. The superior performance of C2 can be ascribed to its robust molecular interactions with bacterial proteins and its effective release in acidic environments, which are typically encountered at infection sites. Such findings underscore the hybrid's potential as a targeted therapeutic approach for combating drug-resistant infections.
CONCLUSION: The synthesized azo-oxazine-tetrazole-CNC nanocomposites, particularly C2, exhibit promising antibacterial efficacy, pH-responsive drug release profiles, and advantageous pharmacokinetic properties. These results substantiate their potential for application in the design of nextgeneration nanocarrier systems to address resistant bacterial infections.