Synthesis and antiprotozoal activity of pyridine thioaryl ethers
By reaction of pyridine nitro derivatives containing a mobile halogen atom with thiols of the benzene series, twelve thioaryl ethers of nitropyridine were obtained. However, 2-chloro-3-nitropyridine and 2-chloro-5-nitropyridine were used as reactive pyridine compounds. The reaction was carried out in dimethylformamide (DMFA) or dimethyl sulfoxide (DMSO) in the presence of bases: sodium ethylate, potash, sodium hydride. Generally, the yields exceeded 90%. The sulfur containing derivatives of aromatic series were 2-mercaptobenzoic acid (compound 1 of Table 1), methyl ester of 2-mercaptobenzoic acid (compounds 2 and 3 of Table 1), compound 3 being obtained by reduction of nitro group of compound 2. Also the amides of 2-mercaptobenzoic acid were used: 3-dimethylaminopropylamide of 2-mercaptobenzoic acid (compound 4 of Table 1), and also the reduction product of compound 4 to 3-aminopyridine derivative (compound 5 of Table 1) and morfolide of 2-mercaptobenzoic acid (compound 6 of Table 1). To make the water-soluble a sodium salt of 2-mercaptobenzoic acid was obtained (compound 7 of Table 1). A number of compounds with the pyridine ring nitrogroup reduced to amine (compounds 8, 10 of Table 1), as well as a number of derivatives containing both free (compounds 9, 10 of Table 1) and acylated amino group (compound 11 of Table 1) were also obtained. We also prepared compound 12 representing a product of interaction of 2-chloro-3-nitropyridine with 2-mercapto-3-acetylpyridine. We should note that the best nitrogroup reductant for the synthesis of compounds 3, 5, 7, and 10 is powdered iron in alcohol medium containing both inorganic and organic acids (hydrochloric or acetic acid). The application of other reducing agents (sodium sulfide and ammonium sulfide) led to strong resinification of the reaction mixture. The compounds were recrystallized from organic solvents (ethyl acetate, benzene, ethanol) for purification. Significant antiprotozoic activity was found in 7 of 12 compounds (58%), with 3-nitro-2-chloropyridine being the most active (7.8 and 3.9 ?g/ml). To enhance the activity, the synthesis of compounds with an amino group in the benzene ring as well as the introduction of both donor and acceptor substituents into the benzene ring is recommended.