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<p>The development of triazole derivatives and coumarin-based molecular hybrids for various biological applications has garnered significant attention in recent years. Therefore in this work, we successfully synthesized two novel coumarin-indole-triazole hybrids: 1-((1-(2-((2-oxo-2&#xa0;H-chromen-4-yl)oxy)ethyl)-1&#xa0;H-1,2,3-triazol-4-yl)methyl)-1&#xa0;H-indole-3 carbaldehyde (4a) and 1-((1-benzyl-1&#xa0;H-1,2,3-triazol-4-yl)methyl)-1&#xa0;H-indole-3-carbaldehyde (5a) and characterized using FTIR, NMR (¹H and ¹³C), and HRMS techniques. Structural and spectral parameters were further validated through density functional theory (DFT) calculations at the B3LYP/6-311 + + G(d, p) level of theory. The antimicrobial potential of these hybrids has been assessed against <i>Staphylococcus aureus</i>, <i>Escherichia coli</i>, and <i>Candida albicans</i>, with tetracycline and fluconazole serving as reference standards. Notably, compound 4a exhibited superior bioactivity, making it a candidate for further investigation. Molecular docking analysis has demonstrated strong interactions of compounds 4a and 5a with thymidylate kinase (TMK) and dihydrofolate reductase (DHFR), showing respective docking scores of − 9.657/–6.931&#xa0;kcal/mol for TMK and − 9.102/–7.775&#xa0;kcal/mol for DHFR. Additionally, Molecular dynamics simulations over 100 ns demonstrated the stability of the 4a-protein complexes, highlighting robust interactions within the active sites of the target proteins. This study underscores the potential of coumarin-indole-triazole hybrids, particularly 4a, as multifunctional therapeutic agents. These hybrids exhibit strong antimicrobial activity, high protein-binding affinity, and stability under dynamic conditions, positioning them as promising candidates against antimicrobial resistance and for expanded therapeutic use.</p> Graphical Abstract <p></p>

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Coumarin-Indole-Triazole Hybrids: Synthesis, Antimicrobial Evaluation, DFT Insights, Molecular Docking, and Dynamics as Potential Antibacterial Agents

  • 期刊论文

  • 发表日期：

    2025年8月8日

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  • Naveed Khan,
  • Mohammed Fayaz Furkhan,
  • Rohith Ramasamy,
  • Beutline Malgija,
  • Habeebullah Thajudeen,
  • V. S. Jamal Ahamed

摘要

The development of triazole derivatives and coumarin-based molecular hybrids for various biological applications has garnered significant attention in recent years. Therefore in this work, we successfully synthesized two novel coumarin-indole-triazole hybrids: 1-((1-(2-((2-oxo-2 H-chromen-4-yl)oxy)ethyl)-1 H-1,2,3-triazol-4-yl)methyl)-1 H-indole-3 carbaldehyde (4a) and 1-((1-benzyl-1 H-1,2,3-triazol-4-yl)methyl)-1 H-indole-3-carbaldehyde (5a) and characterized using FTIR, NMR (¹H and ¹³C), and HRMS techniques. Structural and spectral parameters were further validated through density functional theory (DFT) calculations at the B3LYP/6-311 + + G(d, p) level of theory. The antimicrobial potential of these hybrids has been assessed against Staphylococcus aureus, Escherichia coli, and Candida albicans, with tetracycline and fluconazole serving as reference standards. Notably, compound 4a exhibited superior bioactivity, making it a candidate for further investigation. Molecular docking analysis has demonstrated strong interactions of compounds 4a and 5a with thymidylate kinase (TMK) and dihydrofolate reductase (DHFR), showing respective docking scores of − 9.657/–6.931 kcal/mol for TMK and − 9.102/–7.775 kcal/mol for DHFR. Additionally, Molecular dynamics simulations over 100 ns demonstrated the stability of the 4a-protein complexes, highlighting robust interactions within the active sites of the target proteins. This study underscores the potential of coumarin-indole-triazole hybrids, particularly 4a, as multifunctional therapeutic agents. These hybrids exhibit strong antimicrobial activity, high protein-binding affinity, and stability under dynamic conditions, positioning them as promising candidates against antimicrobial resistance and for expanded therapeutic use.

Graphical Abstract