Anticonvulsant activity and selective inhibition of NAD dependent oxidations in rat brain homogenates by newer mercaptotriazoles

Article abstract of DOI:10.1002/jps.2600660717

Eight 1-(2,6-dimethylphenoxyacetyl)-4-(substituted phenyl)thiosemicarbazides were cyclized to the corresponding 5-(2,6-dimethylphenoxymethyl)-4-(substituted phenyl)-3-mercapto-1,2,-4(4H)-triazoles and 5-(2,6-dimethylphenoxymethyl)-4-(substituted phenyl)-3-[1,2,4(4H)-triazolethioglycolic] acids. These compounds were characterized by their sharp melting points, elemental analyses, and IR spectra and were evaluated for anticonvulsant activity. The degree of protection (range) provided by these thiosemicarbazides, triazoles, and triazolethioglycolic acids at a dose of 100 mg/kg ip against pentylenetetrazol (90 mg/kg sc)-induced convulsions in mice was 10-50, 20-80, and 10-70%, respectively, where cyclization to triazoles increased anticonvulsant activity of the precursor thiosemicarbazides. Increased protection by these compounds against convulsions was generally associated with decreased 24-hr pentylenetetrazol-induced mortality. These compounds exhibited selective in vitro inhibition of nicotinamide adenine dinucleotide (NAD)-dependent oxidation of pyruvate, α-ketoglutarate, and NADH by rat brain homogenates while NAD-independent oxidation of succinate remained unaltered. The presence of added NAD to the reaction mixture during in vitro oxidation of pyruvic acid not only increased the respiratory activity of rat brain homogenates but also decreased the inhibitory effectiveness of thiosemicarbazides, triazoles, and triazolethioglycolic acids. The degree of selective inhibition of NAD-dependent oxidations was unrelated to their anticonvulsant activity.