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

We have investigated the toxicity of a series of 2-pyridylcarboxamidrazones in vitro using a rat liver metabolism system as well as human erythrocytes and mononuclear leucocytes (MNL) as target cells. Of the seven derivatives and four precursors tested, only minimal (<2.3%) metabolism-mediated methaemoglobin was formed by two analogues. However, one of these, a naphthylidene 2-pyridylcarboxamidrazone derivative (compound III), was also directly toxic to human MNLs. This toxicity was partially attenuated by the rat metabolising system and incubation of diethyldithiocarbamate or cimetidine together with compound III and the rat metabolising system suppressed the metabolism-dependent detoxification. This indicated that cytochrome P-450-mediated biotransformation of compound III was preventing its direct toxicity to the MNL. Of the seven derivatives tested, six were low in toxicity to MNL directly and in the presence of a metabolising system. The two compounds which were the most potent anti-mycobacterially, the dimethylpropyl and dimethylethyl benzylidene amidrazone derivatives, were also the least toxic to MNL and erythrocytes. This amidrazone series has shown promise for future development as antituberculosis drugs. (C) 1999 Published by Elsevier Science B.V. All rights reserved.