Antimicrobial activity of [1,2,4]triazolo[4,3-а]pyrazin-8(7h)-one derivatives

Abstract

Today the problem of microbial resistance to antibacterial agents becomes the global one. Antimicrobial drugs that are in the pharmaceutical market do not satisfy the needs of modern treatment regimens, particularly Hospital-acquired infections. Therefore, the search for new and effective means of this pharmacological group is an important task of medical chemistry.  From the literature it is known that derivatives of [1,2,4]triazolo[4,3-a]pyrazine show a wide range of biological actions, including antimicrobial and fungicidal. This makes it relevant microbiological study of primary derivatives of [1,2,4]triazolo[4,3-a]pyrazine for identifying promising compounds of the series and then study it in biological experiment.Using the PASS C&T (Prediction Activity Spectra for Substances: Complex & Training) program and based on published data, we have generated virtual library of derivatives of [1,2,4]triazolo[4,3-a]pyrazine. As a result, we have received 35 new synthetic compounds of 7 series that were not previously described in the literature. Materials and methods. The research of antimicrobial and fungicidal activity of the synthesized compounds was carried out in the laboratory of antimicrobial agents GA "Mechnikov Institute of microbiology and immunology" under the leadership of  PhD, senior scientist V.V.Kazmirchuka. The activity of the synthesized compounds were studied by conventional method of the two-fold serial dilutions in liquid and solid nutrient medium. For primary screening we have used a set of clinical and reference strains of microorganism: Escherichia coli ATCC 25922 (F-50), Staphylococcus aureus ATCC 25923 (F-49), Bacillus anthracoides ATCC 1312, Pseudomonas aeruginosa ATCC 27853, Candida albicans ATCC 885-653. As the reference preparations were chosen Palin - modern antimicrobial agent of class of fluoroquinolones, Nevigramon - nalidixic acid derivative and Fluconazole - modern antifungal agent. Activity of substances determined by the minimum bacteriostatic (MB_stK) and minimal bactericidal (MB_cK) concentrations. All experiments were accompanied by appropriate controls. Results and Discussion. As a result of microbiological screening of  35 compounds we have allowed to identify a number of derivatives of [1,2,4]triazolo[4,3-a]pyrazine-8(7H)-one with antimicrobial and antifungal activity. The most pronounced effect showed compounds that contains in their structure aryl moiety with halogen atom, or N-arylatsetamide group in position 3 or 2 of the heterocycle. Principal condition for the demonstration of antifungal activity is presence of Sulfur atom in the triazole cycle. Conclusions. The substance of the series N⁷-aryl/benzyl-3-thioxo-[1,2,4]triazolo[4,3-а]pyrazin-8(7H)-ones showed the best antimicrobial and antifungal activity of all synthesized compounds. Compound 7-(3-chloro-2-methyl-phenyl)-3-thioxo-[1,2,4]triazolo[4,3-а]pyrazin-8(7Н)-one 4{4} showed high values of antimicrobial activity against gram-negative microorganisms (МB_stК – 12.5-25.0 mkg/ml, МB_cК – 25.0-50.0 mkg/ml) and was the most promising for further development.