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Novel antimicrobial ciprofloxacin-pyridinium quaternary ammonium salts with improved physicochemical properties and DNA gyrase inhibitory activity

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Abstract

New ciprofloxacin/ quaternary ammonium salts 3a–e were designed and synthesized as potential antimicrobial agents. Most of the prepared derivatives showed promising dual antibacterial/antifungal activities. Compound 3e was the most potent and afforded vast spectrum antibacterial activity against S. aureus and most of the tested Gram-negative bacterial strains with MIC values ranging from 1.53–9.54 µg/mL. Moreover, ciprofloxacin and compound 3e induced DNA cleavage in S. aureus DNA gyrase and S. aureus TOPO IV DNA by 1 and 10 µM, respectively. In addition, docking study results agreed with results of DNA cleavage assays where all the tested compounds showed no additional significant interactions over the parent ciprofloxacin. On the other side, compounds 3e and 3f exhibited outstanding antifungal activity better than the reference itraconazole with MICs of 1.87, 4.67, and 11.22 µg/mL, respectively, against Candida. albicans. These data suggest the prevalence of another mechanism in addition to DNA gyrase circumvention, like metal chelation, antibiofilm, and/or improvement of lipophilicity and subsequent penetration.

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Acknowledgements

Authors thank Dr. Rehab Mahmoud Abdel-Baky, professor of Microbiology, Faculty of Pharmacy, Minia University, for her great help in performing antibacterial and antifungal screening studies.

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Authors and Affiliations

  1. Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519, Minia, Egypt

    Hend A. A. Ezelarab, Samar H. Abbas, Gamal El-Din A. Abuo-Rahma & Heba A. Hassan

  2. Department of Pharmaceutics, Faculty of Pharmacy, Minia University, 61519, Minia, Egypt

    Mohammed A. S. Abourehab

  3. Department of Pharmaceutics, Faculty of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia

    Mohammed A. S. Abourehab

  4. Department of Biochemistry, Faculty of Pharmacy, Menoufia University, Menoufia, Egypt

    Mohamed Badr

  5. Chulabhorn Research Institute, Kamphaeng Phet 6 Road, Laksi, Bangkok, 10210, Thailand

    Sanya Sureram & Prasat Kittakoop

  6. Division of Microbiology, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand

    Poonpilas Hongmanee

  7. Chulabhorn Graduate Institute, Program in Chemical Sciences, Chulabhorn Royal Academy, Laksi, Bangkok, 10210, Thailand

    Prasat Kittakoop

  8. Center of Excellence on Environmental Health and Toxicology (EHT), CHE, Ministry of Education, Bangkok, Thailand

    Prasat Kittakoop

  9. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Deraya University, New Minia, 61519, Egypt

    Gamal El-Din A. Abuo-Rahma

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  1. Hend A. A. Ezelarab
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Ezelarab, H.A.A., Abbas, S.H., Abourehab, M.A.S. et al. Novel antimicrobial ciprofloxacin-pyridinium quaternary ammonium salts with improved physicochemical properties and DNA gyrase inhibitory activity. Med Chem Res 30, 2168–2183 (2021). https://doi.org/10.1007/s00044-021-02798-3

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