Department of Organic Chemistry, The Medical University of Silesia, Jagiellońska 4, 41-200 Sosnowiec, Poland.
Eur J Med Chem. 2011 Aug;46(8):3179-89. doi: 10.1016/j.ejmech.2011.05.013. Epub 2011 May 12.
This review summarizes recent medicinal chemistry investigations in vitro and in vivo in search for new phenothiazines of promising biological activities. New phenothiazine derivatives (over 50 main structures) contain dialkylaminoalkyl, cycloaminoalkyl and aminoalkyl substituents and their acyl and sulfonyl derivatives, and other substituents with varied the monocyclic (pyrazole, thiazole, oxadiazole, thiadiazole, tetrazole) and bicyclic (quinolizine, pyrazolopyrimidine, thiazolopyridine, azabicyclononane and spiro[chromanpyrimidine] heterocycles linked directly or via the alkyl chain with the thiazine nitrogen atom or with the benzene ring. The modifications of the tricyclic ring system with the bicyclic homoaromatic ring (naphthalene) and monocyclic and bicyclic azine rings (pyridine, pyrimidine, pyrazine and quinoline) led to compounds of significant biological activities. Recently obtained phenothiazines exhibit promising antibacterial, antifungal, anticancer, antiviral, anti-inflammatory, antimalarial, antifilarial, trypanocidal, anticonvulsant, analgesic, immunosuppressive and multidrug resistance reversal properties. These activities were the results of the actions of phenothiazines on biological systems via the interaction of the pharmacophoric substituent (in some cases of strict length), via the interaction of the multicyclic ring system (π-π interaction, intercalation in DNA) and via the lipophilic character allowing the penetration through the biological membranes. The activities were examined by using various biological systems such as cell lines, bacteria, viruses, parasites, laboratory mice, rats and rabbits, and monolayer and bilayer membranes. Some mechanisms of the actions are discussed. This review shows current tendency in the phenothiazine synthesis (without synthetic routes) and reveals the phenothiazine core to be very potent pharmacophoric moiety which can be a rich source of new compounds having desirable biological activities.
本文综述了近年来在寻找具有潜在生物活性的新型吩噻嗪类化合物方面，在体外和体内进行的药物化学研究。新的吩噻嗪衍生物（超过 50 个主要结构）含有二烷基氨基烷基、环氨基烷基和氨基烷基取代基及其酰基和砜基衍生物，以及其他带有各种单环（吡唑、噻唑、恶二唑、噻二唑、四唑）和双环（喹啉、吡唑并嘧啶、噻唑吡啶、氮杂双环壬烷和螺[色满嘧啶]杂环）取代基的化合物，这些取代基通过烷基链与噻嗪氮原子或苯环直接或间接连接。三环系统与双环同芳香环（萘）以及单环和双环嗪环（吡啶、嘧啶、吡嗪和喹啉）的修饰导致了具有显著生物活性的化合物的产生。最近获得的吩噻嗪类化合物表现出有希望的抗菌、抗真菌、抗癌、抗病毒、抗炎、抗疟疾、抗丝虫、杀锥虫、抗惊厥、镇痛、免疫抑制和多药耐药逆转特性。这些活性是吩噻嗪类化合物通过与药效团取代基（在某些情况下具有严格的长度）相互作用、通过多环系统（π-π 相互作用、DNA 插入）相互作用以及通过允许穿透生物膜的亲脂性特征，对生物系统产生作用的结果。这些活性是通过使用各种生物系统（如细胞系、细菌、病毒、寄生虫、实验小鼠、大鼠和兔子以及单层和双层膜）进行测试的。讨论了一些作用机制。本文综述了目前吩噻嗪类化合物的合成趋势（不包括合成路线），并揭示了吩噻嗪核心是一种非常有效的药效团，它可以成为具有理想生物活性的新型化合物的丰富来源。
