A facile synthesis and antimycobacterial evaluation of novel spiro-pyrido-pyrrolizines and pyrrolidines

An efficient synthesis of 1-methyl-3-[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones was achieved by the reaction of 1-methyl-4-piperidone and aromatic aldehydes in the presence of pyrrolidine under solvent-free microwave irradiation. These dipolarophiles upon cycloaddition with nitrile oxide and azomethine ylides afford stereoselectively novel spiro-isoxazolines, pyrrolizines and pyrrolidines respectively in excellent yields. The spiro compounds were screened for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant M. tuberculosis (MDR-TB) and Mycobacterium smegmatis (MC2) using agar dilution method. Among the synthesized compounds, 1-methyl-4-(2,4-dichlorophenyl)pyrrolo(spiro[2.3″]oxindole)spiro[3.3′]-1′-methylpiperidin-4′-one was found to be the most active with a minimum inhibitory concentration (MIC) of 1.76 and 0.88 μM against MTB and MDR-TB respectively.

Graphical abstract1-Methyl-3-[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones upon cycloaddition with azomethine ylides afford novel spiro-pyrido-pyrrolizines and pyrrolidines in excellent yields stereoselectively. These spiro-heterocycles exhibit promising in vitro antimycobacterial activity against Mycobacterium tuberculosis.Figure optionsDownload full-size imageDownload as PowerPoint slide