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Solid-phase Synthesis of [4.4] Spirocyclic Oximes
Published on: February 6, 2019
A Search for New Amidrazone Derivatives Containing 4-Oxybut-2-enoic Acid Moiety as Antibacterial Agents
Renata Paprocka1, Monika Przybysz1, Kamila Pośpieszyńska1
1Department of Organic Chemistry, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Jurasza Str. 2, 85-089 Bydgoszcz, Poland.
Introduction:
Bacterial diseases pose a significant challenge to modern medicine due to the rapid development of resistance by bacterial strains and the global migration of people, which facilitates the transmission of these diseases. Therefore, there is a need to develop new strategies to combat microorganisms and newer substances that could be used as antibiotics.
Methods:
Six new derivatives, 2a-2f, containing a 4-oxybut-2-enoic acid moiety, were obtained by reacting amidrazones with maleic anhydride. The antimicrobial potency of compounds 2a-2f was studied using the microdilution method against the following bacterial strains: Escherichia coli, Yersinia enterocolitica, Pseudomonas aeruginosa, Staphylococcus aureus, Micrococcus luteus, Enterococcus faecalis, Gordonia rubripertincta, Mycobacterium smegmatis, and the fungal strain Candida albicans. Their antiproliferative activity was tested in cultures of human peripheral blood mononuclear cells stimulated with phytohemagglutinin. The bioavailability parameters of new compounds were predicted using Molinspiration software.
Results:
Derivatives 2a-2c showed the strongest antibacterial activity, especially against Yersinia enterocolitica and Micrococcus luteus. Compounds 2d-2f inhibited the growth of Gordonia rubripertincta. Compounds 2a-2f exhibited low antiproliferative activity towards human peripheral blood mononuclear cells. However, it is necessary to evaluate whether all compounds are well absorbed after oral administration.
Discussion:
The most promising antibacterial activity was demonstrated by derivatives possessing a 2-pyridyl substituent at the R1 position (2a-2c) or a phenyl ring at the R2 position (2a, 2f).
Conclusion:
Compound 2a demonstrated the highest antibacterial activity and selectivity in inhibiting the growth of Y. enterocolitica. Additionally, it exhibited low toxicity to human lymphocytes and demonstrated favorable bioavailability parameters. Therefore, its structure can be used as a starting point for designing new antimicrobials, such as targeted therapies for yersiniosis, beyond traditional antibiotics.
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