Discovery of Antimycobacterial Spiro-piperidin-4-ones: An Atom Economic, Stereoselective Synthesis, and Biological Intervention
journal contributionposted on 25.09.2008, 00:00 by Raju Ranjith Kumar, Subbu Perumal, Palaniappan Senthilkumar, Perumal Yogeeswari, Dharmarajan Sriram
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 α-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 (MC2). 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 μM 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.