Preliminary in vitro toxicological evaluation of a series of 2-pyridylcarboxamidrazone candidate anti-tuberculosis compounds III

We have evaluated the cytotoxicity of a series of novel anti-tubercular 2-p yridyl carboxamidrazones through incubation with human mononuclear leucocyt es (MNL), with and without a rat microsomal metabolising system. Isoniazid (INH), the closest structurally related agent, was used as a positive contr ol. Incubation of the 3-benzyloxy-benzylidene, dimethylpropyl-benzylidene a nd 4-phenyl-benzylidene with MNL showed no significant toxicity in comparis on with either INH or DMSO vehicle control. However, the 4-N,N-dimethylamin o-1-naphthylidene derivative exerted more than sevenfold greater toxicity c ompared with INH, while the 4-N,N-dimethylamino-1-naphthylidene, 2-benzylox y-3-methoxy-benzylidene, 2-t-butylthio-benzylidene and 4-i-propylbenzyliden e derivatives showed toxicity which ranged from five to fourfold that of IN H. In the presence of either rat microsomes with or without NADPH, the 3-be nzyloxy-benzylidene, dimethylpropyl-benzylidene and 4-phenyl-benzylidene de rivatives showed no metabolically-mediated cytotoxicity. The latter two der ivatives showed a combination of low toxicity and considerabe efficacy agai nst Mycobacteria tuberculosis in vitro and show promise for future developm ent. (C) 2001 Elsevier Science B.V. All rights reserved.