Eight l-(2,6-dimethylphenoxyacetyl)-4-(substituted phe-ny1)thiosemicarbazides were cyclized to the corresponding 5-(2,6-dimethylphenoxymethyl)-4-(substituted phenyl)-3-mercapto-l,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 mgkg 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, a-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 wag unrelated to their anticonvulsant activity.
Keyphrases 0 Thiosemicarbazides, various-synthesized, evaluated for anticonvulsant activity and effect on NAD-dependent oxidations, rats 0 Mercaptotriazoles, various-synthesized, evaluated for anticonvulsant activity and effect on NAD-dependent oxidations, rats Triazolethioglycolic acids, various-synthesized, evaluated for anticonvulsant activity and effect on NAD-dependent oxidations, rats Anticonvulsant activity-evaluated in various thiosemicarbazides, mercaptotriazoles, and triazolethioglycolic acids, rats NAD-dependent oxidations-effect of various thiosemicarbazides, mercaptotriazoles, and triazolethioglycolic acids, rat brain homogenates 0 Oxidations, NAD dependent-effect of various thiosemicarbazides, mercaptotriazoles, and triazolethioglycolic acids, rat brain homogenates 0 Structure-activity relationships-various thiosemicarbazides, mercaptotriazoles, and triazolethioglycolic acids evaluated for anticonvulsant activity and effect on NAD-dependent oxidations, rats ' All compounds were analyzed for their carbon, hydrogen, and nitrogen content. Melting points were taken in open capillary tubes with a partial immersion thermometer and are corrected. IR spectra provided support for the structures of these compounds.