Preliminary in vitro toxicological evaluation of a series of 2-pyridylcarboxamidrazone candidate anti-tuberculosis compounds: II(1).
The in vitro toxicity of two amidrazones I [N(1)-(3-benzyloxy-4-methoxybenzylidene)-pyridine-2-carboxamidrazone] and II [N(1)-(4-benzyloxy-3-methoxybenzylidene)-pyridine-2-carboxamidrazone] and their precursors PI (3-benzyloxy-4-methoxybenzaldehyde) and PII (4-benzyloxy-3-methoxybenzaldehyde) was determined using a rat liver metabolism system with human mononuclear leucocytes (MNL) as target cells. The minimum inhibitory concentration for I and II was determined to be between 4 and 8 µg/ml against Mycobacteria fortuitum. In direct contact with human MNL at three concentrations, only II and isoniazid (INH) were significantly more toxic compared with control at 100 and 200 µM. With rat microsomes, INH and PII at 50 µM showed significant toxicity. In the two compartment system without a metabolising system, INH and II were significantly more toxic compared with control and I. In the presence 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 than 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.
Mechanisms of Drug Toxicity Group, Pharmaceutical Sciences Institute, Aston University, Aston Triangle, B4 7ET, Birmingham, UK
MD
Coleman
DL
Rathbone
CR
Endersby
MC
Hovey
KJ
Tims
PA
Lambert
DC
Billington