Ramalingan C, Park Y T, Kabilan S
Department of Chemistry, Kyungpook National University, Daegu 702-701, Korea.
Eur J Med Chem. 2006 Jun;41(6):683-96. doi: 10.1016/j.ejmech.2006.02.005. Epub 2006 Apr 4.
In a wide search program toward new and efficient antimicrobial agents, a series of substituted piperidin-4-one oxime ethers (5a-5k) was synthesized and tested for their in vitro antibacterial and antifungal activities. Also, the structures of these oxime ethers and their relative stereochemistries have been investigated by nuclear magnetic resonance spectroscopy. In all the oxime ethers synthesized, the orientation of the N-O bond of the oxime ether moiety syn to C-5 (E-isomer) was deduced based on (1)H NMR and (13)C NMR spectra. It was found that the sterically less hindered compounds, either C-3 (H) and C-5 (H)- or C-3 (Me) and C-5 (H) -substituted ones 5a, 5c, 5d, 5f, 5g, 5i and 5j prefer chair conformation, whereas the sterically more hindered C-3 (Me) and C-5 (Me) -substituted ones 5b, 5e, 5h, and 5k prefer twist-boat conformation. Among the oxime ethers tested, 1,3,5-trimethyl-2,6-diphenylpiperidin-4-one O-(2-chlorophenylmethyl)oxime (5h) exhibited good antibacterial property against Bacillus subtilis, with minimum inhibitory concentration (MIC) closer to that of reference drug, streptomycin. Compounds, 1,3-dimethyl-2,6-diphenylpiperidin-4-one O-(2-chlorophenylmethyl)oxime (5g) and 1,3-dimethyl-2,6-diphenylpiperidin-4-one O-(2-bromophenylmethyl)oxime (5j) showed potent antifungal activity against Aspergillus flavus and Candida-51, respectively. The later compound 5j is more active than the reference drug while the activity of the former one 5g is similar to that of the reference drug, amphotericin B in terms of MIC. The present results may be used as key steps for the construction of novel chemical entities with better pharmacological profiles than standard drugs.
在一项寻找新型高效抗菌剂的广泛研究计划中，合成了一系列取代的哌啶 - 4 - 酮肟醚（5a - 5k），并对其体外抗菌和抗真菌活性进行了测试。此外，通过核磁共振光谱对这些肟醚的结构及其相对立体化学进行了研究。在所有合成的肟醚中，基于¹H NMR和¹³C NMR光谱推断出肟醚部分的N - O键与C - 5（E - 异构体）顺式的取向。结果发现，空间位阻较小的化合物，即C - 3（H）和C - 5（H） - 或C - 3（Me）和C - 5（H） - 取代的化合物5a、5c、5d、5f、5g、5i和5j倾向于椅式构象，而空间位阻较大的C - 3（Me）和C - 5（Me） - 取代的化合物5b、5e、5h和5k倾向于扭船式构象。在所测试的肟醚中，1,3,5 - 三甲基 - 2,6 - 二苯基哌啶 - 4 - 酮O - （2 - 氯苯基甲基）肟（5h）对枯草芽孢杆菌表现出良好的抗菌性能，其最低抑菌浓度（MIC）接近参考药物链霉素。化合物1,3 - 二甲基 - 2,6 - 二苯基哌啶 - 4 - 酮O - （2 - 氯苯基甲基）肟（5g）和1,3 - 二甲基 - 2,6 - 二苯基哌啶 - 4 - 酮O - （2 - 溴苯基甲基）肟（5j）分别对黄曲霉和念珠菌 - 51表现出强效抗真菌活性。后一种化合物5j比参考药物更具活性，而前一种化合物5g在MIC方面的活性与参考药物两性霉素B相似。目前的结果可作为构建比标准药物具有更好药理特性的新型化学实体的关键步骤。
