Structural modification of ciprofloxacin and norfloxacin for searching new antibiotics to combat drug-resistant bacteria

Authors

DOI:

https://doi.org/10.15587/2519-4852.2021.242997

Keywords:

fluoroquinolones, ciprofloxacin, norfloxacin, synthesis, antibiotic resistance, molecular docking, antibacterial activity

Abstract

The aim of the work. Among all the representatives of four generations of fluoroquinolones ciprofloxacin (CIPRO) and norfloxacin (NOR) remain widely used and prescribed antibiotics in clinical practice. However, the problem of resistance towards them is gradually increasing. Thus, our investigation is dedicated to chemical modification of C-7 position of Ciprofloxacin and Norfloxacin ring as a promising solution to combat antibiotic resistance and open a pathway towards convenient synthesis of new fluoroquinolones derivatives.

Materials and methods. The subjects of the research were N-piperazine-substituted ciprofloxacin and norfloxacin. The methods of molecular docking and organic synthesis were applied in the study. The structures of the obtained compounds were confirmed by 1H NMR, 13C NMR, 19F NMR, LC/MS, IR, UV spectroscopy. The antimicrobial activity was measured by the method of double serial dilutions against Staphylococcus aureus (ATCC 25923), Escherichia coli (ATCC 25922), Bacillus subtilis (ATCC 6633), Pseudomonas aeruginosa (ATCC 27853), Candida albicans (NCTC 885-653) and diffusion in agar method against clinical strains.

The results. 7-(4-(2-Cyanoacetyl)piperazin-1-yl)-1-R-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acids were synthesized and their structures were confirmed. The obtained compounds showed the antibacterial activity on the reference level for double dilution method and exceeded control for “well” method.

Conclusions. The current investigation revealed the promising route for the expanding of the existing fluoroquinolones diversity. Pharmacodynamics and pharmacokinetics changes could be achieved by chemical modifications of C-7 position of the initial ring. Further research utilizing the obtained compounds as starting ones opens a promising way to novel active molecules synthesis and combating the problem of antibiotic resistance

Author Biographies

Halyna Hryhoriv, National University of Pharmacy

PhD

Department of Pharmaceutical Chemistry

Illia Mariutsa, National University of Pharmacy

Postgraduate Student

Department of Organic Chemistry

Sergiy M. Kovalenko, V. N. Karazin Kharkiv National University

Doctor of Chemical Sciences, Professor

Department of Organic Chemistry

Lyudmila Sidorenko, National University of Pharmacy

Doctor of Pharmaceutical Sciences, Professor

Department of Pharmaceutical Chemistry

Lina Perekhoda, National University of Pharmacy

Doctor of Pharmaceutical Sciences, Professor

Department of Medicinal Chemistry

Nataliia Filimonova, National University of Pharmacy

Doctor of Medical Sciences, Professor

Department of Microbiology, Virology and Immunology

Olga Geyderikh, National University of Pharmacy

PhD, Associate Professor

Department of Microbiology, Virology and Immunology

Victoriya Georgiyants, National University of Pharmacy

Doctor of Pharmaceutical Sciences, Professor

Department of Pharmaceutical Chemistry

References

The evolving threat of antimicrobial resistance. Options for action. WHO. Available at: http://apps.who.int/iris/bitstream/handle/10665/44812/9789241503181_eng.pdf?sequence=1

Polk, R. E., Fox, C., Mahoney, A., Letcavage, J., MacDougall, C. (2007). Measurement of Adult Antibacterial Drug Use in 130 US Hospitals: Comparison of Defined Daily Dose and Days of Therapy. Clinical Infectious Diseases, 44 (5), 664–670. doi: http://doi.org/10.1086/511640

Birnbaum, D. (2003). Resistance CCoA. Antimicrobial resistance: a deadly burden no country can afford to ignore. Canada Communicable Disease Report, 29 (18), 157–164.

Feshchenko, Yu. I., Humeniuk, M. I., Denysov, O. S. (2010). Antybiotykorezystentnist mikroorhanizmiv. Stan problemy ta shliakhy vyrishennia. Ukrainskyi khimioterapevtychnyi zhurnal, 1-2 (23), 4–10.

Suaifan, G. A. R. Y., Mohammed, A. A. M. (2019). Fluoroquinolones structural and medicinal developments (2013–2018): Where are we now? Bioorganic & Medicinal Chemistry, 27 (14), 3005–3060. doi: http://doi.org/10.1016/j.bmc.2019.05.038

Bush, N. G., Diez-Santos, I., Abbott, L. R., Maxwell, A. (2020). Quinolones: Mechanism, Lethality and Their Contributions to Antibiotic Resistance. Molecules, 25 (23), 5662. doi: http://doi.org/10.3390/molecules25235662

Dalhoff, A. (2012). Global Fluoroquinolone Resistance Epidemiology and Implictions for Clinical Use. Interdisciplinary Perspectives on Infectious Diseases, 2012, 1–37. doi: http://doi.org/10.1155/2012/976273

Fasugba, O., Gardner, A., Mitchell, B. G., Mnatzaganian, G. (2015). Ciprofloxacin resistance in community- and hospital-acquired Escherichia coli urinary tract infections: a systematic review and meta-analysis of observational studies. BMC Infectious Diseases, 15 (1). doi: http://doi.org/10.1186/s12879-015-1282-4

Savchenko, T. I., Silin, O. V., Kovalenko, S. M., Musatov, V. I., Nikitchenko, V. M., Ivachtchenko, A. V. (2007). Alkylation of 3‐Phenyl‐1H‐pyrazolo[4,3‐c] quinoline: Theoretical Analysis of Regioselectivity. Synthetic Communications, 37 (8), 1321–1330. doi: http://doi.org/10.1080/00397910701227077

Ivachtchenko, A., Silin, O., Savchenko, T., Kovalenko, S., Nikitchenko, V. (2004). Synthesis of 5H-Pyrazolo[4,3-c]quinolines. Heterocycles, 63 (8), 1883–1890. doi: http://doi.org/10.3987/com-04-10092

Bylov, I. E., Bilokin, Y. V., Kovalenko, S. M. (1999). Specific Features of Reactions of 2-Aminobenzotrifluoride and Anthranilates with Ethyl Cyanoacetate – Expeditious Routes to 3-Substituted 4-Amino- and 4-Hydroxyquinolin-2(1H)-Ones. Heterocyclic Communications, 5 (3). doi: http://doi.org/10.1515/hc.1999.5.3.281

Naidu, K. M., Nagesh, H. N., Singh, M., Sriram, D., Yogeeswari, P., Gowri Chandra Sekhar, K. V. (2015). Novel amide and sulphonamide derivatives of 6-(piperazin-1-yl)phenanthridine as potent Mycobacterium tuberculosis H37Rv inhibitors. European Journal of Medicinal Chemistry, 92, 415–426. doi: http://doi.org/10.1016/j.ejmech.2015.01.013

Black, T. A., Mcnicholas, P. M., Walker, S. S., Xu, Y., Ting, P. C. (2008). Pat. WO2008115385A2. Piperazine-substituted pyridazinone derivatives useful as glucan synthase inhibitors. Available at: https://patents.google.com/patent/WO2008115385A2/en

Pushpan, S., Ramachandran, U., Kundu, M., Anantharaman, V., Subramanian, S., Viswanathan R., Tadiparthi, R. et. al. (2008). Novel compounds and their use. Pat. WO2009001192A2. Available at: https://patents.google.com/patent/WO2009001192A2/en

Mohapatra, R. K., El-ajaily, M. M., Alassbaly, F. S., Sarangi, A. K., Das, D., Maihub, A. A. et. al. (2020). DFT, anticancer, antioxidant and molecular docking investigations of some ternary Ni(II) complexes with 2-[(E)-[4-(dimethylamino)phenyl]methyleneamino]phenol. Chemical Papers, 75 (3), 1005–1019. doi: http://doi.org/10.1007/s11696-020-01342-8

Mohapatra, R. K., Perekhoda, L., Azam, M., Suleiman, M., Sarangi, A. K., Semenets, A. et. al. (2021). Computational investigations of three main drugs and their comparison with synthesized compounds as potent inhibitors of SARS-CoV-2 main protease (Mpro): DFT, QSAR, molecular docking, and in silico toxicity analysis. Journal of King Saud University – Science, 33 (2), 101315. doi: http://doi.org/10.1016/j.jksus.2020.101315

Volianskyi, Yu. L., Hrytsenko, I. S., Shyrobokov, V. P. (2004). Vyvchennia spetsyfichnoi aktyvnosti protymikrobnykh likarskykh zasobiv. Kyiv: DFTs MOZ Ukrainy, 38.

Vyznachennia chutlyvosti mikroorhanizmiv do antybakterialnykh preparativ (2007). Metodychni vkazivky, 70.

Sheldon, R. A. (2012). Fundamentals of green chemistry: efficiency in reaction design. Chemical Society Reviews, 41 (4), 1437–1451. doi: http://doi.org/10.1039/c1cs15219j

Sheldon, R. A. (2019). The greening of solvents: Towards sustainable organic synthesis. Current Opinion in Green and Sustainable Chemistry, 18, 13–19. doi: http://doi.org/10.1016/j.cogsc.2018.11.006

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Published

2021-10-29

How to Cite

Hryhoriv, H., Mariutsa, I., Kovalenko, S. M., Sidorenko, L., Perekhoda, L., Filimonova, N., Geyderikh, O., & Georgiyants, V. (2021). Structural modification of ciprofloxacin and norfloxacin for searching new antibiotics to combat drug-resistant bacteria. ScienceRise: Pharmaceutical Science, (5(33), 4–11. https://doi.org/10.15587/2519-4852.2021.242997

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Section

Pharmaceutical Science