Several 10-(1-acetyl-4-arylthiosemicarbazido)phenothiazines and their corresponding cyclized 10-(2-arylimino-3acetylamino-4-thiazolidonyl)phenothiazines were synthesized and characterized by their sharp melting points and elemental analyses. All compounds inhibited nicotinamide adenine dinucleotide (NAD)-dependent oxidation of pyruvate and a-ketoglutarate selectively, whereas NAD-independent oxidation of succinate remained unaltered. All phenothiazine derivatives exhibited anticonvulsant activity, which was reflected by the 2040% protection observed against pentylenetetrazol-induced convulsions in mice. The ability of substituted thiosemicarbazidophenothiazines to inhibit cellular respiratory activity was reduced considerably by cyclization to the corresponding substituted thiazolidinophenothiazines. On the other hand, cyclization generally resulted in increased anticonvulsant activity. Thus, the anticonvulsant activity possessed by these substituted phenothiazines bore no relationship with their ability to inhibit selectively the NAD-dependent oxidations. Selective inhibition of NAD-dependent oxidation of pyruvate and a-ketoglutarate in isolated rat brain mitochondria by some 10-(1-acetyl-4-arylthiosemicarbazido)phenothiazines was concentration dependent and competitive in nature.
Keyphrases Phenothiazines-synthesis, effects on NAD-dependent oxidations, anticonvulsant activity screened, mice Oxidation, NAD dependent-pyruvate and a-ketoglutarate, effect of phenothiazines 0 Anticonvulsant activity-phenothiazines, synthesized, screened, mice Structure-activity relationships-substituted phenothiazines, anticonvulsant activity