Synthesis and antibacterial activity of 3-arylaminomethyl-1-(2-oxo-2-arylethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a] azepin-1-ium bromides and aryl-(4-R1-phenyl-5,6,7,8-tetrahydro-2,2a,8a-triazacyclopenta[cd]azulen-1-ylmethyl)-amines

Authors

DOI:

https://doi.org/10.15587/2519-4852.2021.249480

Keywords:

3-arylaminomethyl-1-(2-oxo-2-arylethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-1-ium bromides, antibacterial activity, in vitro tests, minimum inhibitory concentration

Abstract

The aim of this work is to develop methods of synthesis of 3-arylaminomethyl-1-(2-oxo-2-arylethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-1-ium bromides and aryl-(4-R1-phenyl-5,6,7,8-tetrahydro-2,2a,8a-triazacyclopenta[cd]azulen-1-ylmethyl)-amines and to study their antimicrobial activity against strains of gram-positive and gram-negative bacteria as well as yeast fungi.

Materials and methods. 1Н NMR spectra were recorded on Bruker 400 spectrometer operating at frequency of 400 MHz. Antimicrobial activity of the compounds synthesized was evaluated by their minimum inhibitory concentration (MIC) values.

Results and discussion. The interaction of 3-arylaminomethyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepines with substituted phenacyl bromides produced novel 3-arylaminomethyl-1-(2-oxo-2-arylethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-1-ium bromides. The latter when refluxed in 10 % solution of NaOH gave aryl-(4-R1-phenyl-5,6,7,8-tetrahydro-2,2a,8a-triazacyclopenta[cd]azulen-1-ylmethyl)-amines. The study of antimicrobial activity of the compounds obtained allowed to find derivatives which are active against С. albicans and S. aureus strains. Among the compounds tested 3-[(41-bromophenylamino)-methyl]-1-[2-(4-methoxyphenyl)-2-oxoethyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-1-ium bromide 5cd appeared to be more active than the reference drug Cefixime and displayed close antimicrobial activity as the antibiotic Linezolid.

Conclusions. It was found out that derivatives of 3-arylaminomethyl-1-(2-oxo-2-arylethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-1-ium bromides display broad spectrum of antimicrobial activity and are able to inhibit growth of both bacteria and fungi. S. aureus and C. albicans turned out to be the most sensitive strains to the compounds tested, MIC was in the range of 6.2-25.0 mg/mL. Gram-negative strains of microorganisms were less sensitive to the compounds evaluated and 5fа was the most active derivative displaying antimicrobial activity at the concentration of 50.0 mg/mL. Antimicrobial activity of triazoloazepinium bromide derivatives was similar to that one of Linezolid and Fluconazole reference drugs and more pronounced than the activity of Cefixime.

Hence, the data gathered evidence the feasibility of further study of the antimicrobial properties of the most active compounds in in vivo experiments aiming at assessment of the prospects for the creation of new effective and safe antimicrobial drugs based on them

Author Biographies

Nataliya Demchenko, Taras Shevchenko National University «Chernihiv Collegium»

PhD, Associate Professor

Department of Biology

Zinaida Suvorova, State Institution "Institute of Pharmacology and Toxicology of the National Academy of Medical Sciences of Ukraine"

Leading Engineer

Department of Medical Chemistry

Yuliia Fedchenkova, Nizhyn Mykola Gogol State University

Doctor of Pharmacy, Professor

Department of Chemistry and Pharmacy

Tamara Shpychak, National University of Pharmacy

PhD, Associate Professor

Department of Organic Chemistry

Oleh Shpychak, Institute for Advanced Training of Pharmacy Specialists of National University of Pharmacy

Doctor of Pharmaceutical Sciences, Professor

Department of Industrial Pharmacy and Economy

Ludmila Bobkova, State Institution "Institute of Pharmacology and Toxicology of the National Academy of Medical Sciences of Ukraine"

Doctor of Pharmaceutical Sciences, Chief Researcher

Department of Medicinal Chemistry

Sergii Demchenko, State Institution "Institute of Pharmacology and Toxicology of the National Academy of Medical Sciences of Ukraine"

PhD, Researcher

Department of Pharmacology of Cell Signaling Systems and Experimental Therapy

References

  1. Low, M., Balicer, R. D., Bitterman, H., Raz, R., Lieberman, N. (2014). Unwarranted Use Of Broad-Spectrum Antibiotics. Value in Health, 17 (3), A281. doi: http://doi.org/10.1016/j.jval.2014.03.1635
  2. Antimicrobial resistance: no action today, no cure tomorrow (2011). WHO. Available at: https://www.who.int/dg/speeches/2011/WHD_20110407/en/2011 Last accessed: 18.04.2020
  3. Fair, R. J., Tor, Y. (2014). Antibiotics and Bacterial Resistance in the 21st Century. Perspectives in Medicinal Chemistry, 6, 25–64. doi: http://doi.org/10.4137/pmc.s14459
  4. Melander, R. J., Zurawski, D. V., Melander, C. (2018). Narrow-spectrum antibacterial agents. MedChemComm, 9 (1), 12–21. doi: http://doi.org/10.1039/c7md00528h
  5. Moellering, R. C. (2011). Discovering new antimicrobial agents. International Journal of Antimicrobial Agents, 37 (1), 2–9. doi: http://doi.org/10.1016/j.ijantimicag.2010.08.018
  6. Cully, M. (2014). Redesigned antibiotic combats drug-resistant tuberculosis. Nature Reviews Drug Discovery, 13 (4). doi: http://doi.org/10.1038/nrd4287
  7. Demchenko, S., Lesyk, R., Zuegg, J., Elliott, A. G., Fedchenkova, Y., Suvorova, Z., Demchenko, A. (2020). Synthesis, antibacterial and antifungal activity of new 3-biphenyl-3H-Imidazo[1,2-a]azepin-1-ium bromides. European Journal of Medicinal Chemistry, 201. doi: http://doi.org/10.1016/j.ejmech.2020.112477
  8. Demchenko, S. A., Sukhoveev, V. V., Моsкаlеnко, О. V., Fedchenkova, Y. A., Potebnia, G. P., Demchenko, A. M. (2020). Synthesis and anti-tumor properties of derivatives [4- (41-chlorophenyl)-5,6,7,8-tetrahydro-2,2a,8a-triazacyclopenta[c,d]azulen-1-yl-metil]-para-tolylamine. Farmatsevtychnyi Zhurnal, 4, 69–77. doi: http://doi.org/10.32352/0367-3057.4.20.07
  9. Demchenko, A. M., Nazarenko, K. G., Makei, A. P., Prikhodko, S. V., Kurmakova, I. N., Tretiak, A. P. (2004). Sintez, protivokorrozionnaia i biotsidnaia aktivnost proizvodnykh triazoloazepina. Zhurnal prikladnoi khimii, 77 (5), 794–797.
  10. Demchenko, S. A., Seredinska, N. M., Bukhtіarova, T. A., Bobkova, L. S., Demchenko, A. M. (2019). Pat. No. 119003 UA. 1-Aril-amіnometil-4-fenіl-5,6,7,8-tetragіdro-2,2a,8a-triazatsiklopenta[cd]azuleni, scho proiavliaiut analgetichnu aktivnіst. No. a201707645; declareted: 19.07.2017; published: 10.04.2019, Bul. No. 7.
  11. Metodicheskie ukazaniia MUK 4.2.1890-04 (2004). Opredelenie chuvstvitelnosti mikroorganizmov k antibakterialnym preparatam. Klinicheskaia Mikrobiologiia i Antimikrobnaia KHimioterapiia, 6 (4), 306–359.
  12. Arendrup, M. C., Cuenca-Estrella, M., Lass-Flörl, C., Hope, W. (2012). EUCAST technical note on the EUCAST definitive document EDef 7.2: method for the determination of broth dilution minimum inhibitory concentrations of antifungal agents for yeasts EDef 7.2 (EUCAST-AFST)*. Clinical Microbiology and Infection, 18 (7), 246–247. doi: http://doi.org/10.1111/j.1469-0691.2012.03880.x
  13. Blaskovich, M. A. T., Zuegg, J., Elliott, A. G., Cooper, M. A. (2015). Helping Chemists Discover New Antibiotics. ACS Infectious Diseases, 1 (7), 285–287. doi: http://doi.org/10.1021/acsinfecdis.5b00044
  14. Desselle, M. R., Neale, R., Hansford, K. A., Zuegg, J., Elliott, A. G., Cooper, M. A., Blaskovich, M. A. (2017). Institutional profile: Community for Open Antimicrobial Drug Discovery – crowdsourcing new antibiotics and antifungals. Future Science OA, 3 (2), FSO171. doi: http://doi.org/10.4155/fsoa-2016-0093
  15. Wayne P.A. (2017). CLSI. Performance Standards for Antimicrobial Susceptibility Testing. 27th ed. CLSI supplement M100. Clinical and Laboratory Standards Institute, 250.
  16. Open-access antimicrobial screening program. (2017). Open-access antimicrobial screening program. https://www.co-add.org/
  17. Zhuang, Z., Wan, D., Ding, J., He, S., Zhang, Q., Wang, X. et. al. (2020). Synergistic Activity of Nitroimidazole-Oxazolidinone Conjugates against Anaerobic Bacteria. Molecules, 25 (10), 2431. doi: http://doi.org/10.3390/molecules25102431
  18. Saurabh, A., Kumar, V., Kalaiselvan, V., Kumar, Ap., Thota, P., Sidhu, S., Medhi, B. (2018). Cefixime-associated acute generalized exanthematous pustulosis: Rare cases in India. Indian Journal of Pharmacology, 50 (4), 204–207. doi: http://doi.org/10.4103/ijp.ijp_673_17
  19. Aliaga, L., Moreno, M., Aomar, I., Moya, S., Ceballos, Á., Giner, P. (2017). Treatment of acute uncomplicated cystitis – A clinical review. Clinical and Medical Investigations, 2 (4). doi: http://doi.org/10.15761/cmi.1000142
  20. Sid Ahmed, M. A., Hassan, A. A. I., Abu Jarir, S., Abdel Hadi, H., Bansal, D., Abdul Wahab, A. (2019). Emergence of Multidrug- and Pandrug- Resistant Pseudomonas aeruginosa from Five Hospitals in Qatar. Infection Prevention in Practice, 1 (3-4), 100027. doi: http://doi.org/10.1016/j.infpip.2019.100027
  21. Ishida, K., Fernandes Rodrigues, J. C., Cammerer, S., Urbina, J. A., Gilbert, I., de Souza, W., Rozental, S. (2011). Synthetic arylquinuclidine derivatives exhibit antifungal activity against Candida albicans, Candida tropicalis and Candida parapsilopsis. Annals of Clinical Microbiology and Antimicrobials, 10 (1). doi: http://doi.org/10.1186/1476-0711-10-3
  22. Emami, S., Shojapour, S., Faramarzi, M. A., Samadi, N., Irannejad, H. (2013). Synthesis, in vitro antifungal activity and in silico study of 3-(1,2,4-triazol-1-yl)flavanones. European Journal of Medicinal Chemistry, 66, 480–488. doi: http://doi.org/10.1016/j.ejmech.2013.06.008

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Published

2021-12-30

How to Cite

Demchenko, N., Suvorova, Z., Fedchenkova, Y., Shpychak, T., Shpychak, O., Bobkova, L., & Demchenko, S. (2021). Synthesis and antibacterial activity of 3-arylaminomethyl-1-(2-oxo-2-arylethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a] azepin-1-ium bromides and aryl-(4-R1-phenyl-5,6,7,8-tetrahydro-2,2a,8a-triazacyclopenta[cd]azulen-1-ylmethyl)-amines . ScienceRise: Pharmaceutical Science, (6 (34), 51–57. https://doi.org/10.15587/2519-4852.2021.249480

Issue

No. 6 (34) (2021)

Section

Pharmaceutical Science

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Copyright (c) 2021 Nataliya Demchenko, Zinaida Suvorova, Yuliia Fedchenkova, Tamara Shpychak, Oleh Shpychak, Ludmila Bobkova, Sergii Demchenko

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