Introduction-
Oxazolidinone is a five-member heterocyclic ring with several promising biological applications like including antibacterial, antituberculosis, anticancer, anti-inflammatory, neurologic, and metabolic diseases, among other areas. Among the three possible isomers, 2-oxazolidinone is the most investigated in drug discovery. Linezolid (LZD) was pioneered as the first approved drug containing an oxazolidinone ring as the pharmacophore group. However, most oxazolidinone derivatives reported in recent decades have not reached the initial stages of drug development, despite their promising pharmacological applications. This review article compiled the efforts of medicinal chemists who have explored this scaffold over the past decades and highlighted the potential of the class for medicinal chemistry.
Fig 1
Oxazolidinones as antibacterial agents
Bacteria develop resistance naturally over time as they are exposed to antibiotics. There is a growing concern about multidrug-resistant pathogens, Enterococcus spp, S. aureus, K. pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp. In 2011, Khera et al. described a series of 1,2,4-triazolo[4,3-α] pyrimidine oxazolidinone with potent inhibitory activity against Gram-positive bacteria. Initially, they disclosed a series of 22 derivatives and found compound 8 (Fig.2) to be the most promising with minimum inhibitory concentration (MIC) values of 1.0 μg mL−1 against E. faecalis ATCC 29212 and S. aureus ATCC 25923 and 0.5 μg mL−1 against S. aureus MRSA 43300 and S. epidermedis ATCC 12228. Compound 8 also showed metabolic stability in the human liver microsome.
Fig 2
Oxazolidinones as antitubercular agents
Mycobacterium tuberculosis is one of the deadliest pathogens documented in the history of human civilization. Oxazolidinone derivatives, especially LZD analogues, have been extensively studied as antitubercular agents. In 2017, benzoxazinyl–oxazolidinone 55 (Fig.3) was discovered as a potent anti-TB compound with MIC90 of 0.391 μg mL−1 against M. tuberculosis H37Rv and less than 0.50 μg mL−1 against drug-resistant strains. It did not show toxicity against HepG2 cells (IC50 > 64 μg mL−1) nor inhibitory activity against the hERG K+ channel (IC50 > 30 μM. Subsequently, compound 55 went through a hit-to-lead optimization medicinal campaign in an attempt to identify an analogue (Compound 56) with improved anti-TB activity, reduced toxicity, and improved drug-like properties. Recently, the same group reported the discovery of a new tricyclic benzo [1,3] oxazinyl–oxazolidinone 57 as a new anti-TB lead.
Fig 3
Oxazolidinones as anti-cancer agents
Oxazolidinones are one of the classes within the large chemical universe that are systematically researched for the treatment of cancer. Mutant isocitrate dehydrogenases 1 (mIDH1) and 2 (mIDH2) have been extensively studied as promising anticancer targets. Compound 72 (IDH125) (Fig.4) was the first hit identified by high-throughput screening (HTS). The X-ray cocrystal structure of 72 in the homodimer of IDH1R132H demonstrated the importance that the oxazolidinone ring has in the active binding conformation. Following an iterative hit-to-lead medicinal chemistry campaign exploring the phenyl ring, the researchers developed compound 73 (IDH889) (Fig.4) as a new lead with improved activity and PK properties.
Fig 4
Oxazolidinones in neurological disorders
Huang et al. reported an oxazolidinone acting as a positive allosteric modulator (PAM) of the metabotropic glutamate receptor subtype 5 (mGluR5) for the treatment of schizophrenia. Oxazolidinone 93 (BMS-955829) (Fig.5) exhibited an EC50 value of 2.6 nM against PAM, excellent mGluR5 binding affinity (Ki 1.6 nM), and high selectivity for the mGluR5 subtype. It showed in vivo efficacy in mice models of schizophrenia. Further, drugability profiling highlighted its safety profile and favourable brain penetration. The LZD derivative 96 (Fig.6) suppressed chemically induced seizures (in vitro seizure model in the rat hippocampus) by reducing action potential firing and excitatory postsynaptic transmission highlighting the potential of the class as antiepileptic agents.
Fig 5
Fig 6
Future Perspectives and Conclusion-
The discovery of LZD and its approval by the FDA in the 2000 revealed oxazolidinones as promising scaffolds in the toolbox of medicinal chemistry. Since then, oxazolidinones have been extensively investigated in medicinal chemistry, and numerous LZD analogues have been developed. LZD was indeed a pioneering drug, being the first fully synthetic small molecule able to inhibit the bacterial protein synthesis. As an example, the tricyclic benzo [1,3]oxazinyl-oxazolidinone 57 shows promise as a potential preclinical anti-TB agent, while oxazolidinones 74, 75 and 78 are used in anticancer therapy. Oxazolidinones 93 and 96 have found application in the treatment of schizophrenia and epilepsy, highlighting the versatility of this class of compounds.
In conclusion, 2-oxazolidinones are a widely investigated and still fascinating class of compounds even if a large number of oxazolidinone derivatives have not been successful in advancing the drug development pipeline, they still represent interesting starting points for future optimization or drug repurposing strategies.
Reference-
Guilherme Felipe Santos Fernandes, Cauê Benito Scarim, Seong-Heun Kim, Jingyue Wu and Daniele Castagnolo,
Oxazolidinones as versatile scaffolds in medicinal chemistry
RSC Medicinal Chemistry
Volume 14
2023
DOI-
By Debangana Banerjee
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