Phenylisoxazole-3/5-Carbaldehyde Isonicotinylhydrazone Derivatives: Synthesis, Characterization, and Antitubercular Activity
Fernando Carrasco, Wilfredo Hernández, Oscar Chupayo, Patricia Sheen, Mirko Zimic, Jorge Coronel, Celedonio M. Álvarez, Sergio Ferrero, Sandra Oramas‐Royo, Evgenia Spodine, Jesús M. Rodilla, Juan Z. Dávalos
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, 1H-NMR, 13C-NMR, and mass spectral data. The 2D NMR (1H-1H NOESY) analysis of 1 and 2 confirmed that these compounds in acetone-d6 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 μM) with respect to the isoniazid drug (MIC = 0.91 μM) against the H37Rv sensitive strain. Compounds 6 (X = 4′-OCH3) and 7 (X = 4′-CH3) with MIC values of 12.41 and 13.06 μM, respectively, were about two times more cytotoxic, compared with isoniazid, against the resistant strain TB DM97.