Abstract
1,3-Dipolar cycloaddition of enantiomerically pure (
R)-(1-phenylethyl)-3,5-bis[(
E)-arylmethylidene]tetrahydro-4(1
H)-pyridinones with nitrile oxides affords di- and trispiroheterocycles regio- and stereoselectively in moderate yields and these spiroheterocycles display good anti-tubercular activities against
Mycobacterium tuberculosis H37Rv (MTB) and multi-drug-resistant
M. tuberculosis (MDR-TB).
Enantiomerically pure (
R)-(1-phenylethyl)-3,5-bis[(
E)-arylmethylidene]tetrahydro-4(1
H)-pyridinones were synthesized for the first time, and their 1,3-dipolar cycloaddition with nitrile oxides affording di- and trispiroheterocycles regio- and stereoselectively in moderate yields was investigated. These compounds were evaluated against
Mycobacterium tuberculosis H37Rv (MTB) and multi-drug-resistant
M. tuberculosis (MDR-TB). Among the compounds screened, the dispiroheterocycle, namely, (5
R,6
R,10
S)-3,9-bis(4-chlorophenyl)-10-(2,4-dichlorophenyl)-14-[(
E)-(2,4-dichlorophenyl)methylidene]-12-[(
R)-1-phenylethyl]-1,4,7-trioxa-2,8,12-tri-azadispiro[4.0.4.4]tetradeca-2,8-diene
5m was found to possess the maximum activity with MIC of 0.49
μM against MTB, being 9.6 and 15.6 times more potent than ciprofloxacin and ethambutol, respectively. Against MDR-TB,
5m displayed maximum activity with an MIC of 0.49
μM, with it thus being more active than rifampicin, isoniazid, ciprofloxacin and ethambutol by 7.8, 23, 77 and 124 times, respectively.