Design, synthesis and biological evaluation of novel azaspiro analogs of linezolid as antibacterial and antitubercular agents

• Synthesis of novel series of azaspiro analogues of linezolid.
• Anti microbial activity studies of azaspiro analogues of linezolid.
• Anti mycobacterial screening of azaspiro analogues of linezolid on Mycobacterium tuberculosis H37Ra (ATCC 25177) and Mycobacterium bovis BCG (ATCC 35734).
• The N-acetyl derivative 18 was identified as lead molecule possessing good antitubercular profile.

The design, synthesis and antimicrobial evaluation of a novel series of azaspiro analogues of linezolid (1) have been described. Linezolid comprises of a morpholine ring which is known for its metabolism-related liabilities. Therefore, the key modification made in the linezolid structure was the replacement of morpholine moiety with its bioisostere, 2-oxa-6-azaspiro[3.3]heptane. Furthermore, the replacement of N-acetyl terminal of 1 with various aromatic or aliphatic functionalities was carried out. The title compounds were evaluated against a panel of Gram-positive and Gram-negative bacteria and Mycobacterium tuberculosis. Subsequent structure-activity relationship (SAR) studies identified several compounds with mixed antibacterial and antitubercular profiles. Compound 22 (IC50 0.72, 0.51, 0.88, 0.49 μg/mL for Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis, respectively) exhibited similar antibacterial profile as 1. The N-acetyl derivative 18 was similar to 1 in antitubercular profile. Thus, the present study successfully demonstrated the use of azaspiro substructure in the medicinal chemistry of antibacterial and antitubercular agents.

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