Synthesis and antiprotozoal activity of 2-phenoxy derivatives of pyridine

Abstract

The aim of the present work is to synthesize phenoxypyridine derivatives and to screen substances with a high level of biological activity within the series of synthesized compounds, which is essential for solving the problem of overcoming the growing drug resistance of bacteria and protozoa. The interaction of 2-chloro-5-nitro- and 2-chloro-3-nitro-pyridine with aromatic aldehydes containing phenolic hydroxyl gave 15 pyridine series aryl ethers in high yields when reacted in dimethylformamide (DMFA) or dimethyl sulfoxide (DMSO) in the presence of bases. In the reaction we used phenolic derivative of kojic acid (compound 1 of Table 1), a number of benzene series aldehydes with different substituents: 3-methoxy-4-hydroxybenzaldehyde (compound 2 of Table 1), 4-hydroxybenzaldehyde (compound 3 of Table 1), 2,4-dihydroxybenzaldehyde (compound 5 of Table 1), 3-methoxy-4-hydroxybenzaldehyde (compound 7 of Table 1 ), salicylic aldehyde (compound 11 of Table 1), 3,4-dihydroxybenzaldehyde (compound 12 of Table 1), vanillin (compound 13 of Table 1), and compound 15 (Table 1) of the benzene series with two hydroxyl and aldehyde groups. As well as benzene-type aldehydes, the methyl ester of salicylic acid (compound 4 of Table 1), 4-hydroxymethylphenol (compound 6 of Table 1), 4-acetylphenol (compound 8 of Table 1), and 3-hydroxy benzoic acid (compound 14 of Table 1) were used. In the reaction, in addition to the above compounds, 7-hydroxycoumarin (compound 9 of Table 1) and semicarbazide-4-hydroxybenzaldehyde (compound 10 of Table 1) were also used. Their purification was performed by recrystallization from organic solvents (ethyl acetate, benzene, ethanol, and isopropanol). The obtained compounds were studied as part of the institute's search for compounds to expand the range of active substances with protistoсid and antibacterial activity with low toxicity. Synthesized compounds have pronounced antiprotozoal activity against Colpoda steinii. the most active compound contains a nitro group in the 3rd position of the pyridine ring as well as an aldehyde and hydroxyl group in the benzene ring. The minimum protistocidal concentration of this compound is 0.9 µg/ml, which is 60 fold more active than toltrazuril and 8 fold more active than chloroquine. This compound is recommended for extended toxicological and pharmacological studies.