title: Preliminary in vitro toxicological evaluation of a series of 2-pyridylcarboxamidrazone candidate anti-tuberculosis compounds III.
abstract: We have evaluated the cytotoxicity of a series of novel anti-tubercular 2-pyridyl carboxamidrazones through incubation with human mononuclear leucocytes (MNL), with and without a rat microsomal metabolising system. Isoniazid (INH), the closest structurally related agent, was used as a positive control. Incubation of the 3-benzyloxy-benzylidene, dimethylpropyl-benzylidene and 4-phenyl-benzylidene with MNL showed no significant toxicity in comparison with either INH or DMSO vehicle control. However, the 4-N,N-dimethylamino-1-naphthylidene derivative exerted more than sevenfold greater toxicity compared with INH, while the 4-N,N-dimethylamino-1-naphthylidene, 2-benzyloxy-3-methoxy-benzylidene, 2-t-butylthio-benzylidene and 4-i-propyl-benzylidene derivatives showed toxicity which ranged from five to fourfold that of INH. In the presence of either rat microsomes with or without NADPH, the 3-benzyloxy-benzylidene, dimethylpropyl-benzylidene and 4-phenyl-benzylidene derivatives showed no metabolically-mediated cytotoxicity. The latter two derivatives showed a combination of low toxicity and considerabe efficacy against Mycobacteria tuberculosis in vitro and show promise for future development.
authors.affiliation: Mechanisms of Drug Toxicity Group, Pharmaceutical Sciences Institute, Aston University, Aston Triangle, B4 7ET, Birmingham, UK
authors.forename: M D.
authors.initials: MD
authors.lastname: Coleman
authors.forename: D L.
authors.initials: DL
authors.lastname: Rathbone
authors.forename: R
authors.initials: R
authors.lastname: Chima
authors.forename: P A.
authors.initials: PA
authors.lastname: Lambert
authors.forename: D C.
authors.initials: DC
authors.lastname: Billington