Kumar Raju Ranjith, Perumal Subbu, Senthilkumar Palaniappan, Yogeeswari Perumal, Sriram Dharmarajan
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625021, Tamil Nadu, India.
J Med Chem. 2008 Sep 25;51(18):5731-5. doi: 10.1021/jm800545k. Epub 2008 Aug 21.
An atom economic and stereoselective synthesis of several spiro-piperidin-4-ones through 1,3-dipolar cycloaddition of azomethine ylides generated in situ from isatin and alpha-amino acids viz . proline, phenylglycine, and sarcosine to a series of 1-methyl-3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones is described. These compounds were evaluated for their in vitro and in vivo activity against Mycobacterium tuberculosis H37Rv (MTB), multidrug resistant Mycobacterium tuberculosis (MDR-TB), and Mycobacterium smegmatis (MC(2)). Compound 4-(4-fluorophenyl)-5-phenylpyrrolo(spiro[2.3'']oxindole)spiro[3.3']-1'-methyl-5'-(4-fluorophenylmethylidene)piperidin-4'-one (4e) was found to be the most active in vitro with a MIC value of 0.07 microM against MTB and was 5.1 and 67.2 times more potent than isoniazid and ciprofloxacin, respectively. In vivo, compound 4e decreased the bacterial load in lung and spleen tissues with 1.30 and 3.73-log 10 protections respectively and was considered to be promising in reducing bacterial count in lung and spleen tissues.
描述了一种原子经济且立体选择性的合成几种螺-哌啶-4-酮的方法，该方法是通过将异吲哚酮与α-氨基酸（即脯氨酸、苯甘氨酸和肌氨酸）原位生成的甲亚胺叶立德与一系列1-甲基-3,5-双[（E）-芳基亚甲基]四氢-4（1H）-吡啶酮进行1,3-偶极环加成反应。对这些化合物针对结核分枝杆菌H37Rv（MTB）、耐多药结核分枝杆菌（MDR-TB）和耻垢分枝杆菌（MC（2））的体外和体内活性进行了评估。发现化合物4-（4-氟苯基）-5-苯基吡咯并（螺[2.3'']吲哚酮）螺[3.3']-1'-甲基-5'-（4-氟苯基亚甲基）哌啶-4'-酮（4e）在体外活性最高，对MTB的MIC值为0.07 microM，分别比异烟肼和环丙沙星强5.1倍和67.2倍。在体内，化合物4e分别使肺和脾组织中的细菌载量降低了1.30和3.73个对数10，被认为在降低肺和脾组织中的细菌数量方面很有前景。
