Скринінгові дослідження антибактеріальної дії нових похідних оксіамінів

O.М. Волощук



O. M. Voloshchuk


The rapid spread of resistance to antimicrobial drugs from the one side and decrease the number of new antibiotics, especially for the treatment of infections caused by "ESKAPE" pathogens (Enterococcus, Staphylococcus, Klebsiella, Acinetobacter, Pseudomonas, Enterobacter) from the other, determines the relevance of creation new, safe and highly effective antimicrobial drugs and introduction of them into clinical practice.

The creation of antimicrobial drugs through screening of known compounds by chemical modification of their molecules is one of the promising ways of obtaining new derivatives with distinct biological properties. A comprehensive study carbocyclic compounds, which include oxiamine derivatives, gives reason to consider this class of substances as a promising source of highly active molecules. It is known that these compounds are part of enzymes, proteins, nucleic acids, and are involved in many chemical processes of living cells, which exhibit various biological effects.

The aim of research was to evaluate the antimicrobial activity of 53 new oxiamine derivatives synthesized in Institute of organic chemistry of NAS of Ukraine. Depending from the radicals structure all test compounds were divided into four different group: 27 adamantane containing compounds, 7 bornyl/norbornyl containing compounds, 8 compounds with cyclic substituents in alkoxy group and 7 compounds with alicyclic substituents in alkoxy group.

These substances were investigated for the first time in to the antibacterial activity against museum strains of gram-positive and gram-negative bacteria, including representatives of the "ESCAPE" pathogens: Enterococcus, Staphylococcus, Klebsiella, Pseudomonas. Antibacterial activity of the tested compounds was determined by the establishing their minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) with using method of serial dilutions in liquid nutrient medium.

According to the results of the study, the greatest number of substances with antibacterial properties was detected among adamantane containing compounds. Gram-positive and gram-negative bacteria were sensitive to 11 from the 27 investigated compounds of this group. The value of their MIC against Enterococcus faecalis ATSS 6873 ranged from 31,25 µg/ml to 62.5 µg/ml. Gram-negative bacteria were resistant to compounds of this group's,  their MIC fluctuated in wide limits – from 3.8 µg/ml to > 500 µg/ml. Also, among adamantane containing compounds was identified  1- ( adamantyl-1-methoxy ) - 3 - ( 2,2,6,6-tetramethylpiperidine ) – 2 - propanol hydrochloride (compound № 11), that is equally effective against gram-negative and gram-positive microorganisms. MBC of compound № 11 towards S. aureus was 5,6 mg/ml. The MBC of compound № 11 towards Ps.aeruginosa and Kl.pneumoniae was in the same range as that of the known drug ofloxacin (62,5 µg/ml and 7.8 µg/ml, respectively).

Among the group bornyl/norbornyl containing substances only compound № 51 showed a moderate activity against S. aureus ATSS 25923, her MIC towards  this bacteria was 62.5 µg/ml. All the studied substances from this group of compounds proved to be inactive towards representatives of gram-negative enterobacteria, their MIC were more than 500 µg/ml.

Among the group of compounds with cyclic substituents in alkoxy group only compound № 41 showed moderate antibacterial activity against Enterococcus faecalis ATSS 6873– its MIC was 62.5 µg/ml. All gram-negative reference strains of bacteria were insensitive or resistant to the action of compounds of this group, their MIC ranged from 125 ág/ml to 500 µg/ml or more.

All compounds with alicyclic substituents in alkoxy group except of compound № 47 was inactive against the museum test strains of bacteria. Antibacterial activity of compound № 47 was detected towards gram-positive bacteria only. MIC this substance against S. aureus ATSS 25923 and Enterococcus faecalis ATSS 6873 were 15.6 µg/ml and 31,25 µg/ml respectively.

In conclusion, a number of substances that have shown concentratio- and structure-dependent antimicrobial activity against pathogenic and conditionally pathogenic gram-positive and gram-negative bacteria were identified among the studied groups of  new oxiamine derivatives. The greatest number substances with antibacterial activity was determined in the group of adamantane containing compounds. Among substances of this group's identified compound -1-(adamantan–1–methoxy)–3-(2,2,6,6–tetramethylpiperidine)-2-propanol hydrochloride, which showed high antibacterial activity in the same concentrations that comparison drug ofloxacin. In each groups of tested compounds from the second, third and fourth were identified only one substance with antimicrobial properties.

Thus, evaluation antibacterial activity of the synthesized compounds with pronounced antibacterial properties would be promising against clinical isolates of bacteria. Mechanism of action compounds with pronounced antibacterial properties would be appropriate detailed study also.

Keywords: oxiamine derivatives, antibacterial activity, "ESKAPE" pathogens

Повний текст:



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