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<p>A new set of azo-coumarin benzoxazole hybrids was easily obtained by one-pot, multicomponent reaction of substituted azo-2-hydroxybenzaldehydes, o-aminophenol, and ethyl cyanoacetate under mild conditions and catalytic amount of acetic acid and glycerol. The protocol provided the target compounds in large quantities with benefits like shorter reaction time, simple work-up and reduced amounts of waste. The synthesized hybrids were structurally elucidated by IR and NMR (¹H, ¹³C, DEPT-135) and mass spectrometric methods. Based on the in vitro antimicrobial evaluation the hybrids exhibit strong inhibitory activity, with Compound <b>2f</b> <i>R</i> = 2-OCH<sub>3</sub> being the most effective derivative. It showed a very low 0.007&#xa0;mg/mL against <i>Candida albicans</i> and remarkable 0.014&#xa0;µg/mL Minimum Inhibitory Concentration (MIC) values against <i>S. aureus</i> and <i>E. coli</i>. The compounds in the series demonstrated a generally stronger antifungal activity compared to their antibacterial effects, with MICs for <i>Candida albicans</i> ranging from 0.007 to 0.14&#xa0;µg/mL. In order to offer a very thorough mechanistic view of its broad-spectrum antimicrobial potency, the molecular docking studies were extended to incorporate pertinent target proteins of all the three microorganisms tested. Compound <b>2f</b> had high binding affinities with <i>S. aureus</i> (PDB ID: 1MWT, -9.3&#xa0;kcal/mol), <i>E. coli</i> (PDB ID: 1KZN, -7.4&#xa0;kcal/mol) and <i>C. albicans</i> (PDB ID: 5TZ1, -8.8&#xa0;kcal/mol). Interaction analysis in the <i>S. aureus</i> target was found to have a few conventional hydrogen bonds with the major amino acid residues (GLU447, GLU460, THR582, ALA642, SER643) and other stabilizing contact with HIS583 and MET641. Besides, the compound also established stable complexes in the active sites of the <i>E. coli</i> and <i>C. albicans</i> targets by a strong linkage of both π -interactions and electrostatic forces. All these multi-target interactions supported with excellent shape fitting are suggestive of good addition of the ligand into the active sites and justifies its wide foundational biological profile. In general, the obtained biological and computational outcomes also emphasize synthesized azo3-coumarin benzoxazole hybrids as the promising ones to continue the drug development research.</p>

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Novel Azo-Functionalized Benzoxazole–Coumarin Hybrids: Synthesis, Spectral Characterization, Antibacterial Evaluation, and Molecular Docking Insights

  • 期刊论文

  • 发表日期：

    2026年3月9日

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  • Rezan Huseen Hama Salih,
  • Farouq Emam Hawaiz

摘要

A new set of azo-coumarin benzoxazole hybrids was easily obtained by one-pot, multicomponent reaction of substituted azo-2-hydroxybenzaldehydes, o-aminophenol, and ethyl cyanoacetate under mild conditions and catalytic amount of acetic acid and glycerol. The protocol provided the target compounds in large quantities with benefits like shorter reaction time, simple work-up and reduced amounts of waste. The synthesized hybrids were structurally elucidated by IR and NMR (¹H, ¹³C, DEPT-135) and mass spectrometric methods. Based on the in vitro antimicrobial evaluation the hybrids exhibit strong inhibitory activity, with Compound 2f R = 2-OCH3 being the most effective derivative. It showed a very low 0.007 mg/mL against Candida albicans and remarkable 0.014 µg/mL Minimum Inhibitory Concentration (MIC) values against S. aureus and E. coli. The compounds in the series demonstrated a generally stronger antifungal activity compared to their antibacterial effects, with MICs for Candida albicans ranging from 0.007 to 0.14 µg/mL. In order to offer a very thorough mechanistic view of its broad-spectrum antimicrobial potency, the molecular docking studies were extended to incorporate pertinent target proteins of all the three microorganisms tested. Compound 2f had high binding affinities with S. aureus (PDB ID: 1MWT, -9.3 kcal/mol), E. coli (PDB ID: 1KZN, -7.4 kcal/mol) and C. albicans (PDB ID: 5TZ1, -8.8 kcal/mol). Interaction analysis in the S. aureus target was found to have a few conventional hydrogen bonds with the major amino acid residues (GLU447, GLU460, THR582, ALA642, SER643) and other stabilizing contact with HIS583 and MET641. Besides, the compound also established stable complexes in the active sites of the E. coli and C. albicans targets by a strong linkage of both π -interactions and electrostatic forces. All these multi-target interactions supported with excellent shape fitting are suggestive of good addition of the ligand into the active sites and justifies its wide foundational biological profile. In general, the obtained biological and computational outcomes also emphasize synthesized azo3-coumarin benzoxazole hybrids as the promising ones to continue the drug development research.