An atom economic synthesis and antitubercular evaluation of novel spiro-cyclohexanones

The 1,3-dipolar cycloaddition of azomethine ylides derived from acenaphthenequinone and α-amino acids viz. sarcosine, phenylglycine, 1,3-thiazolane-4-carboxylic acid and proline to a series of 2,6-bis[(E)-arylmethylidene]cyclohexanones afforded novel spiro-heterocycles chemo-, regio- and stereoselectively in quantitative yields. These compounds were screened for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB) using agar dilution method. Two compounds, 4-(2,4-dichlorophenyl)-5-phenylpyrrolo(spiro[2.2″]acenaphthene-1″-one)spiro[3.2′]-6′-(2,4-dichlorophenylmethylidene)cyclohexanone (4i) and spiro[5.2″]acenaphthene-1″-onespiro[6.2′]-6′-(2,4-dichlorophenylmethylidene)cyclohexanone-7-(2,4-dichlorophenyl)tetrahydro-1H-pyrrolo[1,2-c][1,3]thiazole (5i) display maximum activity in vitro with a MIC value of 0.40 μg/mL against MTB and were 4 and 15.6 times more potent than ethambutol and pyrazinamide, respectively.

Graphical abstractTwenty eight spiro-cyclohexanones were synthesized via 1,3-dipolar cycloaddition of azomethine ylides to a series of 2,6-bis[(E)-arylmethylidene]cyclohexanones and were screened for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB) using agar dilution method. Two compounds, 4-(2,4-dichloro-phenyl)-5-phenylpyrrolo-(spiro[2.2″]acenaphthene-1″-one)-spiro[3.2′]-6′-(2,4-dichlorophenylmethylidene)-cyclohexanone (4i) and spiro-[5.2″]acenaphthene-1″-one-spiro[6.2′]-6′-(2,4-dichlorophenylmethylidene)-cyclohexanone-7-(2,4-dichlorophenyl)tetrahydro-1H-pyrrolo[1,2-c][1,3]thiazole (5i) display maximum activity in vitro with MIC of 0.4 μg/mL and were 4 and 15 times more potent than ethambutol and pyrazinamide, respectively.Figure optionsDownload full-size imageDownload as PowerPoint slide