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 metha emoglobin was formed by two analogues. However, one of these, a naphthylide ne 2-pyridylcarboxamidrazone derivative (compound III), was also directly t oxic to human MNLs. This toxicity was partially attenuated by the rat metab olising system and incubation of diethyldithiocarbamate or cimetidine toget her with compound III and the rat metabolising system suppressed the metabo lism-dependent detoxification. This indicated that cytochrome P-450-mediate d biotransformation of compound III was preventing its direct toxicity to t he MNL. Of the seven derivatives tested, six were low in toxicity to MNL di rectly and in the presence of a metabolising system. The two compounds whic h were the most potent anti-mycobacterially, the dimethylpropyl and dimethy lethyl benzylidene amidrazone derivatives, were also the least toxic to MNL and erythrocytes. This amidrazone series has shown promise for future deve lopment as antituberculosis drugs. (C) 1999 Published by Elsevier Science B .V. All rights reserved.