1,3-Dipolar cycloaddition of C-aryl-N-phenylnitrones to (R)-1-(1-phenylethyl)-3-[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones: synthesis and antimycobacterial evaluation of enantiomerically pure spiroisoxazolidines.
A series of novel enantiomerically pure spiroisoxazolidines were synthesized regioselectively by the 1,3-dipolar cycloaddition of C-aryl-N-phenylnitrones to (R)-1-(1-phenylethyl)-3-[(E)-arylmethylidene]-tetrahydro-4(1H)-pyridinones. These compounds have been screened for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB) using agar dilution method. Among the twenty two compounds screened, (3S,4S,5R)-3,4-di(4-methylphenyl)-2-phenyl-7-[(R)-1-phenylethyl]-1-oxa-2,7-diazaspiro[4.5]decan-10-one (3e) was found to possess the maximum activity with MIC of 3.02 microM, being 2.5 times more potent than the first-line anti-TB drug ethambutol. For comparison, a series of ten enantiomerically pure spirooxazolines were also screened, among which (4R,5S)-3,4-bis(4-chlorophenyl)-7-[(R)-1-phenylethyl]-1-oxa-2,7-diazaspiro[4.5]dec-2-en-10-one and (4R,5S)-4-(2-chlorophenyl)-3-(4-chlorophenyl)-7-[(R)-1-phenylethyl]-1-oxa-2,7-diazaspiro[4.5]dec-2-en-10-one were found to display maximum activity with MIC of 3.25 microM.
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Palkalai Nagar, Madurai 625021, India.
Raju Suresh
RS
Kumar
Subbu
S
Perumal
Krithika Arun
KA
Shetty
Perumal
P
Yogeeswari
Dharmarajan
D
Sriram
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D055808:Drug Discovery; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D009589:Nitrogen Oxides / Q000737:chemistry*; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011728:Pyridones / Q000737:chemistry*; D013237:Stereoisomerism
D000900:Anti-Bacterial Agents; D009589:Nitrogen Oxides; D010080:Oxazoles; D011728:Pyridones; C015388:nitrones