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  3. Design, synthesis, antibacterial evaluation, and molecular modelling studies of 1,2,3-triazole-linked coumarin-vanillin hybrids as potential DNA gyrase and topoisomerase IV inhibitors

Design, synthesis, antibacterial evaluation, and molecular modelling studies of 1,2,3-triazole-linked coumarin-vanillin hybrids as potential DNA gyrase and topoisomerase IV inhibitors

  • Bioorg Chem. 2025 Jul 29:164:108815. doi: 10.1016/j.bioorg.2025.108815.
Aanchal Khanna 1,  Anmol Narang 2,  Vishakha Thakur 3,  Karanvir Singh 4,  Nitish Kumar 5,  Rubaldeep Kaur 1,  Megha 6,  Alok Raj 7,  Meenakshi Devi 7,  Jyoti 1,  Rupali Rana 1,  Anchal Sharma 1,  Harmandeep Kaur 1,  Prabhpreet Singh 3,  Sukhraj Kaur 2,  Preet Mohinder Singh Bedi 8
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab 143005, India.
  • 2 Department of Microbiology, Guru Nanak Dev University, Amritsar, Punjab 143005, India.
  • 3 Department of Chemistry, Centre of Advanced Study, Guru Nanak Dev University, Amritsar, Punjab 143005, India.
  • 4 Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab 143005, India. Electronic address: karanvirsinghrajput@gmail.com.
  • 5 Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab 143005, India. Electronic address: nitishsanotra@live.com.
  • 6 Department of Chemistry, Centre of Advanced Study, Guru Nanak Dev University, Amritsar, Punjab 143005, India; Swami Premanand Mahavidyalaya, Mukerian, Punjab 144211, India.
  • 7 Kwality Pharmaceuticals Ltd., Amritsar, Punjab 143601, India.
  • 8 Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab 143005, India; Drug and Pollution Testing Lab, Guru Nanak Dev University, Amritsar, Punjab 143005, India. Electronic address: preet.pharma@gndu.ac.in.
PMID: 40743706 DOI: 10.1016/j.bioorg.2025.108815
Abstract

The escalating threat of antimicrobial resistance necessitates the urgent development of novel therapeutic agents targeting essential Bacterial enzymes. In this study, a new series of 1,2,3-triazole-linked coumarin-vanillin hybrids was rationally designed and synthesized, integrating the bioactive moieties of coumarin and vanillin derivatives via the click chemistry technique. The synthesized compounds (AK1-AK30) were thoroughly characterized by 1H, 13C NMR, FT-IR, and HR-MS spectroscopic techniques. All the compounds exhibited broad-spectrum Antibacterial efficacy against both gram-positive and gram-negative pathogens. AK19 demonstrated minimum inhibitory concentrations (MIC) of 1.9 μM against Bacillus subtilis and clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA), and superior efficacy compared to ciprofloxacin against Pseudomonas aeruginosa and Shigella boydii. Additionally, it exhibited significant biofilm inhibition against B. subtilis and MRSA. Mechanistically, AK19 showed strong inhibition against Escherichia coli DNA gyrase and E. coli Topoisomerase with IC50 values of 0.783 ± 0.04 μM and 7.136 ± 1.03 μM, respectively. Molecular docking and molecular dynamics simulations further substantiated these results by demonstrating stable binding of AK19 within the active sites of the targeted Enzymes, with favourable binding free energies (ΔG = - 48 KJ/Mol and - 29 KJ/Mol, respectively). Additionally, bovine serum albumin (BSA) binding studies and ADME profiling indicated desirable pharmacokinetic characteristics. The overall results underscore the AK19 as a promising lead compound for the development of next-generation Antibacterial agents targeting DNA gyrase and Topoisomerase IV.

Keywords

Antibacterial; Coumarin; DNA gyrase; Topoisomerase IV; Triazole.

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