Assessment of Antimycobacterial Activity of Newly Synthesized Pyrimidine Derivatives Against Mycobacterium tuberculosis

Abstract

Background. The current trend of growing antibiotic resistance among pathogenic microorganisms remains one of the urgent and significant problems of mankind. The constant spread of resistant strains of microorganisms requires the development of innovative methods and the search for medicinal compounds with a highly effective mechanism of action. One of these multi-resistant pathogens that are difficult to eradicate is the causative agent of tuberculosis — Mycobacterium tuberculosis. The aim is to study the effect of newly synthesized pyrimidine derivatives on the growth of Mycobacterium tuberculosis culture, as well as on the structural changes in cells.Material and methods. In order to assess the effect of a number of pyrimidine derivatives on the growth of Mycobacterium tuberculosis culture, 6 samples of 5-(arylmethylene) hexahydropyrimidine-2,4,6-triones (TAG1 — TAG6), 7 samples of 5-hetarylmethylidene-2,4,6-triones (TAG7 — TAG13), and 2 new samples of 3-(2-Benzyloxy-2-oxoethyl)quinazoline-4(3H)-one and 3-[2-(1-Naphthyl)-2-oxoethyl]quinazoline-4(3H)-one were screened under the laboratory ciphers VMA-13-03 and VMA-13-04 in the course of the study. M.tuberculosis H37RV strain was used as a test culture; it was provided by the bacteriological laboratory of the Regional Infectious Clinical Hospital named after A. M. Nichoga. A 4-week culture of M.tuberculosis, synchronized by cold (+4°C) for 72 hours, was used to prepare a suspension of mycobacteria. The number of mycobacteria in the suspension was determined using the McFarland 0.5 turbidity standard. 0.2 ml of M.tuberculosis working suspension was added to each tube of a series of successive dilutions of the studied substances, including the control. The study was carried out in 4 series of replicates. The minimum bactericidal concentration of the compounds, at which no colony growth was detected, as well as the minimum inhibitory concentration, at which mycobacterium growth was delayed by 50% compared to the control, were determined. Smears were prepared from the sediment for staining using theZiehl-Neelsen method to determine the presence of acid-resistant and non-acid-resistant forms of mycobacteria, as well as to study the effect of pyrimidines and a comparison drug on structural changes in M.tuberculosis cells.Results. In the course of the study, the TAG4, TAG6, and TAG8 compounds were found to have the closest antibacterial activity to the comparison drug isoniazid, according to the indicator of mycobacteria growth retardation. The greatest bactericidal activity against M.tuberculosis was observed in TAG4, TAG7, and VMA–13–04. The remaining compounds have shown minimal inhibitory effect on the growth of M.tuberculosis. Microscopic studies have shown that under the influence of TAG3, TAG4, TAG7, TAG12, VMA-13-03, and VMA-13-04, the main structural components of M.tuberculosis cells undergo fragmentation and morphological changes compared to mycobacterium cells without exposure.Conclusion. As a result, it was found that all the studied compounds possess antimycobacterial activity. Compounds under the laboratory ciphers TAG1, TAG4, TAG7, and TAG13 were comparable to isoniazid by the nature of the inhibitory effect on the growth of M.tuberculosis, and the TAG3 compound even slightly exceeded the effect of the comparison drug. Compounds under the laboratory codes VMA-13-03, and VMA-13-04 had the least pronounced anti-tuberculosis effect. Compounds under the laboratory codes TAG5, TAG6, TAG11, and TAG12 showed the least antimycobacterial activity.