Synthesis and modification of 2-[8-R1-9-R2-10-R3-3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazoline-6-yl)thio]acetic acids aimed at searching effective substances with the antibacterial and antifungal activity

I. S. Nosulenko, O. Yu. Voskoboynik, G. G. Berest, S. I. Kovalenko, O. M. Kamyshnyi, N. M. Polishchuk

Abstract


In the present paper, 50 new derivatives 2-[8-R1-9-R2-10-R3-3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazoline-6-yl)thio]acetic acids have been described. It was shown that alkylation of potassium 8-R1-9-R2-10-R3-3-R-2-oxo-2H-[1,2,4]triazino­[2,3-c]quinazolin-6-thiolates by chloracetic acid, chloracetamide, N-R4-chloracet­amides and chloracetonitrile yielded corresponding 2-[8-R1-9-R2-10-R3-3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazoline-6-yl)thio]acetic acids, their amides and nitriles. For corresponding acids and nitriles, alternative synthetic approaches were elaborated. Limitations of synthetic approaches aimed to the synthesis of target compounds were also discussed. Thus, it was shown, that amides of derivatives 2-[8-R1-9-R2-10-R3-3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazoline-6-yl)thio]acetic acids could not be prepared by amonolysis of corresponding ester as result of low reactivity of mentioned compounds. Also, in was claimed that synthesis of nitriles via dehydration of proper amides with phosphorous-oxychloride in dichlormethane was successful not in all cases. Mentioned fact caused by low yields and problems with isolation of target compound from reaction mixture. The structures of synthesized compounds were determined by 1H, 13C NMR, LC–MS analysis. Synthesized compounds were tested for antimicrobial and antifungal activity using standard test cultures: Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853 and Candida albicans ATCC 885-653. It was shown, that synthesized compounds exhibit high antimicrobial activity against St. aureus (compounds 3.3-3.6, 4.3-4.6, 4.7, 4.8, 4.13-4.16; MIC 12,5-25 µg/ml) and C. albicans (compounds 4.13, 4.14; MIC 12,5 µg/ml). The “structure-activity” relationships were discussed.

Keywords


synthesis; quinazolines; triazines; antibacterial action; antifungal action

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References


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DOI: https://doi.org/10.24959/88925

Abbreviated key title: Vìsn. farm.

ISSN 2415-8844 (Online), ISSN 1562-7241 (Print)