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

The in vitro toxicity of two amidrazones I [N-1-(3-benzyloxy-4-methoxybenzy lidene)-pyridine-2-carboamidrazone] and II [N-1-(4-benzyloxy-3-methoxybenzy lidene)-yridine-2-carboxamidrazone] and their precursors PI (3-benzyloxy-4- methoxybenzaldehyde) and PII (4-benzyloxy-3-methoxybenzaldehyde) was determ ined using a rat liver metabolism system with human mononuclear leucocytes (MNL) as target cells. The minimum inhibitory concentration for I and II wa s determined to be between 4 and 8 mu g/ml against Mycobacteria fortuitum. In direct contact with human MNL at three concentrations, only II and isoni azid (INH) were significantly more toxic compared with control at 100 and 2 00 mu M. With rat microsomes, INH and PII at 50 mu M showed significant tox icity. In the two compartment system without a metabolising system, INH and II were significantly more toxic compared with control and I. In the prese nce of the metabolising system, INH and PI were more toxic than control and INH was more toxic compared with I. II was not significantly more toxic th an control. INH caused more cell death in the presence of the metabolising system compared with its absence. Less toxic compared with INH, compound I has shown promise for future development as an antituberculosis drug. (C) 2 000 Elsevier Science B.V. All rights reserved.