Mutagenicity of condensed pyridazines with different substituents

A total of 24 compounds were prepared by introducing an N-oxide, a hydrazino group, a methoxy group or a chloro group into 3 kinds of condensed pyridazines: pyrido[3,4-d]pyridazines, pyrido[2,3-d]pyridazines and phthalazines. The mutagenicity of these 24 compounds was assessed by the Ames method using two tester strains (Salmonella typhimurium TA98 and TA100). No mutagenic activity was detected with any of the 3 condensed pyridazines without substituents or any of the 5 condensed pyridazines with a methoxy group. The compounds with N-oxide in the pyridazine ring showed no or only very weak mutagenicity. However, when an oxide was introduced into the nitrogen of the pyridine ring, the mutagenicity against strain TA98 was higher than that of any other test compound. All compounds with a hydrazino group were mutagenic against strains TA98 and TA100, irrespective of the presence or absence of S9 mix-induced metabolic activation. 1-Hydrazinophthalazine (hydralazine) which has been clinically used as an antihypertensive agent was weakly mutagenic. The introduction of a chloro group increased the bactericidal effects of the condensed pyridazines, thus hampering the assessment of mutagenicity. A majority of the compounds which were found to be mutagenic in this study required no metabolic activation with S9 mix.