title: Design, synthesis and biological evaluation of novel azaspiro analogs of linezolid as antibacterial and antitubercular agents.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Piramal Enterprises Ltd., 1, Nirlon Complex, Goregaon (East), Mumbai, 400063, India.
authors.forename: Pradip K
authors.initials: PK
authors.lastname: Gadekar
authors.affiliation: Department of Medicinal Chemistry, Piramal Enterprises Ltd., 1, Nirlon Complex, Goregaon (East), Mumbai, 400063, India.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Roychowdhury
authors.affiliation: Department of Pharmaceutical Chemistry, SPP School of Pharmacy and Technology Management, SVKM's NMIMS, V. L. Mehta Road, Vile Parle (West), Mumbai, 400 056, India.
authors.forename: Prashant S
authors.initials: PS
authors.lastname: Kharkar
authors.affiliation: Combi Chem-Bio Resource Centre, Division of Organic Chemistry, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune, 411 008, India; School of Health Sciences, University of KwaZulu Natal, Westville Campus, Durban 4000, South Africa.
authors.forename: Vijay M
authors.initials: VM
authors.lastname: Khedkar
authors.affiliation: Combi Chem-Bio Resource Centre, Division of Organic Chemistry, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune, 411 008, India.
authors.forename: Manisha
authors.initials: M
authors.lastname: Arkile
authors.affiliation: Combi Chem-Bio Resource Centre, Division of Organic Chemistry, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune, 411 008, India.
authors.forename: Hardik
authors.initials: H
authors.lastname: Manek
authors.affiliation: Combi Chem-Bio Resource Centre, Division of Organic Chemistry, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune, 411 008, India.
authors.forename: Dhiman
authors.initials: D
authors.lastname: Sarkar
authors.affiliation: Department of Medicinal Chemistry, Piramal Enterprises Ltd., 1, Nirlon Complex, Goregaon (East), Mumbai, 400063, India.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Center for Organic and Medicinal Chemistry, School of Advanced Sciences, VIT University, Vellore, 632014, Tamil Nadu, India.
authors.forename: V
authors.initials: V
authors.lastname: Vijayakumar
authors.affiliation: Center for Organic and Medicinal Chemistry, School of Advanced Sciences, VIT University, Vellore, 632014, Tamil Nadu, India. Electronic address: sarveswari@gmail.com.
authors.forename: S
authors.initials: S
authors.lastname: Sarveswari
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D003198:Computer Simulation; D015195:Drug Design; D000069349:Linezolid / Q000737:chemistry*; D008826:Microbial Sensitivity Tests; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D013141:Spiro Compounds; D000069349:Linezolid
keywords: Antibacterial; Antitubercular; Azaspiro; Bioisostere; MRSA (methicillin-resistant Staphylococcus aureus); Morpholine; VRE (vancomycin-resistant enterococci)