Discovery of antimycobacterial spiro-piperidin-4-ones: an atom economic, stereoselective synthesis, and biological intervention.
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 alpha-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 (MC(2)). 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 microM 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.
Kumar
Raju Ranjith
RR
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625021, Tamil Nadu, India.
Perumal
Subbu
S
Senthilkumar
Palaniappan
P
Yogeeswari
Perumal
P
Sriram
Dharmarajan
D
D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013237:Stereoisomerism
D000995:Antitubercular Agents; D010880:Piperidines