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

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 rep...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2016-10, Vol.122, p.475-487
Main Authors: Gadekar, Pradip K., Roychowdhury, Abhijit, Kharkar, Prashant S., Khedkar, Vijay M., Arkile, Manisha, Manek, Hardik, Sarkar, Dhiman, Sharma, Rajiv, Vijayakumar, V., Sarveswari, S.
Format: Article
Language:English
Subjects:
Antibacterial
Antitubercular
Antitubercular Agents - chemical synthesis
Antitubercular Agents - chemistry
Antitubercular Agents - pharmacology
Azaspiro
Bioisostere
Chemistry Techniques, Synthetic
Computer Simulation
Drug Design
Linezolid - chemistry
Microbial Sensitivity Tests
Morpholine
MRSA (methicillin-resistant Staphylococcus aureus)
Spiro Compounds - chemical synthesis
Spiro Compounds - chemistry
Spiro Compounds - pharmacology
Structure-Activity Relationship
VRE (vancomycin-resistant enterococci)
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Summary: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. [Display omitted] •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.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2016.07.001