Singh S P, Ali B, Auyong T K, Parmar S S, De Boer B
J Pharm Sci. 1976 Mar;65(3):391-6. doi: 10.1002/jps.2600650319.
Several Several 10-(1-acetyl-4-arylthiosemicarbazido) phenothiazines and their corresponding cyclized 10-(2-arylimino-3-acetylamino-4-thiazolidonyl)phenothiazines were synthetized and characterized by their sharp melting points and elemental analyses. All compounds inhibited nicotinamide adenine dinucleotide (NAD)-dependent oxidation of pyruvate and alpha-ketoglutarate selectively, whereas NAD-independent oxidation of succinate remained unaltered. All phenothiazine derivatives exhibited anticonvulsant activity, which was reflected by the 20-60% 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 alpha-ketoglutarate in isolated rat brain mitochondria by some 10-(1-acetyl-4-arylthiosemicarbazido) phenothiazines was concentration dependent and competitive in nature.
合成了几种10 -（1 - 乙酰基 - 4 - 芳基硫代氨基脲基）吩噻嗪及其相应的环化产物10 -（2 - 芳基亚氨基 - 3 - 乙酰氨基 - 4 - 噻唑烷酮基）吩噻嗪，并通过其尖锐的熔点和元素分析对其进行了表征。所有化合物均选择性地抑制烟酰胺腺嘌呤二核苷酸（NAD）依赖的丙酮酸和α - 酮戊二酸氧化，而琥珀酸的NAD非依赖氧化则保持不变。所有吩噻嗪衍生物均表现出抗惊厥活性，这在对小鼠戊四氮诱导惊厥的20 - 60%保护率中得到体现。取代硫代氨基脲基吩噻嗪环化为相应的取代噻唑烷酮基吩噻嗪后，其抑制细胞呼吸活性的能力显著降低。另一方面，环化通常会导致抗惊厥活性增加。因此，这些取代吩噻嗪的抗惊厥活性与其选择性抑制NAD依赖氧化的能力无关。一些10 -（1 - 乙酰基 - 4 - 芳基硫代氨基脲基）吩噻嗪对分离的大鼠脑线粒体中丙酮酸和α - 酮戊二酸的NAD依赖氧化的选择性抑制呈浓度依赖性且本质上具有竞争性。
