Fundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos-Far Manguinhos, Manguinhos, Rio de Janeiro, Brazil; Instituto de Química, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro, Brazil.
Arch Pharm (Weinheim). 2014 Jun;347(6):432-48. doi: 10.1002/ardp.201300417. Epub 2014 Mar 10.
A series of N-acylhydrazonyl-thienyl derivatives (compounds 2 and 3), mainly of the type 2-(aryl-CH=N-NHCOCH2 )-thiene (2: aryl = substituted-phenyl; 3: aryl = heteroaryl) were evaluated against Mycobacterium tuberculosis. Particularly active compound was 3 (heteroaryl = 5-nitrothien-2-yl or 5-nitrofuran-2-yl) with MIC values of 8.5 and 9.0 μM, respectively. Moderately active compounds were compound 3 (heteroaryl = pyridin-2-yl) and compound 2 containing aryl = 2- or 4-hydroxyphenyl groups, with MIC values between 170 and 408 μM. Compound 2 containing OMe, H, F, Cl, Br, CN, and NO2 substituents and compound 3 (heteroaryl = furan-2-yl, thien-2-yl, pyrrol-2-yl, imidazol-2-yl, pyridin-3-yl, and pyridin-4-yl) were all inactive. Clearly, there is no correlation of activity with the electronic effects of the substituents. The activities suggest different modes of biological action of the compounds having nitro-heteroaryl groups, on the one hand, and the 2-hydroxyphenyl or pyridin-2-yl substituents, on the other hand. Compounds having 2- or 4-hydroxyphenyl, 2-hydroxy-5-nitrophenyl, or 4-hydroxy-3-chlorophenyl were less cytotoxic than ethambutol. It is important to notice that compound 3 (aryl = 5-NO2 -furan-2-yl) exhibited a promising therapeutic index (TI = 1093.90), with a value 4.4 less than that of ethambutol. Compounds 2 and 3 exist in DMSO or MeOD solutions as mixtures of EC(O)N /EC=N and ZC(O)N /EC=N conformers.
一系列 N-酰基腙噻吩衍生物（化合物 2 和 3），主要为 2-（芳基-CH=N-NHCOCH2）-噻吩（2：芳基=取代苯基；3：芳基=杂芳基），被评估了对结核分枝杆菌的活性。特别活跃的化合物是 3（杂芳基=5-硝基噻吩-2-基或 5-硝基呋喃-2-基），其 MIC 值分别为 8.5 和 9.0 μM。中度活性的化合物是 3（杂芳基=吡啶-2-基）和 2（芳基=2-或 4-羟基苯基），其 MIC 值在 170 和 408 μM 之间。含有 OMe、H、F、Cl、Br、CN 和 NO2 取代基的化合物 2 和 3（杂芳基=呋喃-2-基、噻吩-2-基、吡咯-2-基、咪唑-2-基、吡啶-3-基和吡啶-4-基）均无活性。显然，活性与取代基的电子效应之间没有相关性。这些活性表明，具有硝基杂芳基的化合物和具有 2-羟基苯基或吡啶-2-基取代基的化合物的生物作用模式不同。具有 2-或 4-羟基苯基、2-羟基-5-硝基苯基或 4-羟基-3-氯苯基的化合物比乙胺丁醇的细胞毒性更小。值得注意的是，化合物 3（芳基=5-NO2-呋喃-2-基）表现出有希望的治疗指数（TI=1093.90），比乙胺丁醇的值低 4.4。化合物 2 和 3 在 DMSO 或 MeOD 溶液中以 EC(O)N/EC=N 和 ZC(O)N/EC=N 构象的混合物形式存在。
