Phenylisoxazole-3/5-carbaldehyde isonicotinylhydrazone derivatives: synthesis, characterization, and antitubercular activity

Abstract

Eight new phenylisoxazole isoniazid derivatives, 3-(2 '-fluorophenyl)isoxazole-5-carbaldehyde isonicotinylhydrazone (1), 3-(2 '-methoxyphenyl)isoxazole-5-carbaldehyde isonicotinylhydrazone (2), 3-(2 '-chlorophenyl)isoxazole-5-carbaldehyde isonicotinylhydrazone (3), 3-(3 '-clorophenyl)isoxazole-5-carbaldehyde isonicotinylhydrazone (4), 3-(4 '-bromophenyl)isoxazole-5-carbaldehyde isonicotinylhydrazone (5), 5-(4 '-methoxiphenyl)isoxazole-3-carbaldehyde isonicotinylhydrazone (6), 5-(4 '-methylphenyl)isoxazole-3-carbaldehyde isonicotinylhydrazone (7), and 5-(4 '-clorophenyl)isoxazole-3-carbaldehyde isonicotinylhydrazone (8), have been synthesized and characterized by FT-IR, H-1-NMR, C-13-NMR, and mass spectral data. The 2D NMR (H-1-H-1 NOESY) analysis of 1 and 2 confirmed that these compounds in acetone-d(6) are in the trans(E) isomeric form. This evidence is supported by computational calculations which were performed for compounds 1-8, using DFT/B3LYP level with the 6-311++G(d,p) basis set. The in vitro antituberculous activity of all the synthesized compounds was determined against the Mycobacterium tuberculosis standard strains: sensitive H37Rv (ATCC-27294) and resistant TB DM97. All the compounds exhibited moderate bioactivity (MIC = 0.34-0.41 mu M) with respect to the isoniazid drug (MIC = 0.91 mu M) against the H37Rv sensitive strain. Compounds 6 (X = 4 '-OCH3) and 7 (X = 4 '-CH3) with MIC values of 12.41 and 13.06 mu M, respectively, were about two times more cytotoxic, compared with isoniazid, against the resistant strain TB DM97.