2-Oxazolidone Explained

2-Oxazolidone is a heterocyclic organic compound containing both nitrogen and oxygen in a 5-membered ring.

Oxazolidinones

Evans auxiliaries

Oxazolidinones are a class of compounds containing 2-oxazolidone in the structure. In chemistry, they are useful as Evans auxiliaries, which are used for chiral synthesis. Usually, the acid chloride substrate reacts with the oxazolidinone to form an imide. Substituents at the 4 and 5 position of the oxazolidinone direct any aldol reaction to the alpha position of the carbonyl of the substrate.

Pharmaceuticals

Oxazolidinones are mainly used as antimicrobials. The antibacterial effect of oxazolidinones is by working as protein synthesis inhibitors, targeting an early step involving the binding of N-formylmethionyl-tRNA to the ribosome.^[1] (See Linezolid#Pharmacodynamics)

Some of the most important oxazolidinones are antibiotics.^[2]

Examples of antibiotic oxazolidinones include:

• Linezolid (Zyvox), which is available for intravenous administration and also has the advantage of having excellent oral bioavailability.
• Posizolid, which appears to have excellent, targeted bactericidal activity against all common gram-positive bacteria, regardless of resistance to other classes of antibiotics.^[3]

• Tedizolid, (Sivextro) which is approved for acute skin infections
• Radezolid (RX-1741) has completed some phase-II clinical trials.^[4]
• Cycloserine is a second line drug against tuberculosis. Note that cycloserine, while technically an oxazolidone, has a different mechanism of action and substantially different properties from the aforementioned compounds.
• Contezolid (MRX-I) has reported phase 1 data^[5] and phase III data.^[6] In 2021, a new drug summary was published by ADIS Press.^[7] In June 2021, marketing approval was granted by the Chinese National Medical Products Administration (NMPA) for use of oral contezolid in moderate to severe complicated skin and skin structure infections.^[8] In June 2022, contezolid oral tablets and contezolid acefosamil IV (a prodrug of contezolid) began Phase 3 global clinical trials in moderate to severe diabetic foot infections.^[9] An additional global Phase 3 study is planned for acute bacterial skin and skin structure infections (ABSSSI) for the combination of contezolid and contezolid acefosamil.
• An oxazolidinone derivative used for other purposes is rivaroxaban, which is approved by the FDA for venous thromboembolism prophylaxis.

History

The first ever used oxazolidinone was cycloserine (4-amino-1,2-oxazolidin-3-one), a second line drug against tuberculosis since 1956.^[10]

Developed during the nineties when several bacterial strains were becoming resistant against such antibiotics as vancomycin. Linezolid (Zyvox) is the first approved agent in the class (FDA approval April 2000).

The first commercially available 1,3-oxazolidinone antibiotic was linezolid, discovered and developed by Pharmacia & Upjohn.

In 2002 AstraZeneca began investigating posizolid, which is in clinical trials for use in humans.^[11]

See also

• Oxazolidine – the ring without the carbonyl group
• Oxazolone – the unsaturated analogues

References

1. Shinabarger . D. . 10.1517/13543784.8.8.1195 . Mechanism of action of the oxazolidinone antibacterial agents . Expert Opinion on Investigational Drugs . 8 . 8 . 1195–1202 . 1999 . 15992144.
2. Book: Antibiotics: Targets, Mechanisms and Resistance. A Chemist’s Survey of Different Antibiotic Classes. Sonia Ilaria Maffioli. Claudio O. Gualerzi . Letizia Brandi . Attilio Fabbretti . Cynthia L. Pon. 2014. Wiley-VCH. 9783527659685.
3. Wookey, A. . Turner, P. J. . Greenhalgh, J. M. . Eastwood, M. . Clarke, J. . Sefton, C. . AZD2563, a novel oxazolidinone: definition of antibacterial spectrum, assessment of bactericidal potential and the impact of miscellaneous factors on activity in vitro . Clinical Microbiology and Infection . 2004 . 10 . 3 . 247–254 . 15008947 . 10.1111/j.1198-743X.2004.00770.x. free .
4. Web site: Rx 1741 . Rib-X Pharmaceuticals . 2009 . 2009-05-17 . dead . https://web.archive.org/web/20090226201337/http://www.rib-x.com/pipeline/rx_1741 . 2009-02-26 .
5. 10.1021/jm401931e . 57 . 11 . New Potent Antibacterial Oxazolidinone (MRX-I) with an Improved Class Safety Profile . 2014 . Journal of Medicinal Chemistry . 4487–4497 . Gordeev . Mikhail F. . Yuan . Zhengyu Y.. 24694071 .
6. 10.1093/jac/dkac073 . A Phase III multicentre, randomized, double-blind trial to evaluate the efficacy and safety of oral contezolid versus linezolid in adults with complicated skin and soft tissue infections . 2022 . Zhao . Xu . Huang . Haihui . Yuan . Hong . Yuan . Zhengyu . Zhang . Yingyuan . Journal of Antimicrobial Chemotherapy . 77 . 6 . 1762–1769 . 35265985 .
7. 10.1007/s40265-021-01576-0 . Contezolid: First Approval . 2021 . Hoy . Sheridan M. . Drugs . 81 . 13 . 1587–1591 . 34365606 . 8536612 .
8. Web site: China NMPA Approves MicuRx's Contezolid for Treatment of Drug-Resistant Bacterial Infection - MicuRx Pharmaceuticals, Inc .
9. ClinicalTrials.gov Identifier: NCT05369052
10. A. W. Frahm, H. H. J. Hager, F. v. Bruchhausen, M. Albinus, H. Hager: Hagers Handbuch der pharmazeutischen Praxis: Folgeband 4: Stoffe A-K., Birkhäuser, 1999,
11. Karpiuk . I . Tyski . S . Looking for the new preparations for antibacterial therapy. V. New antimicrobial agents from the oxazolidinones groups in clinical trials . Przeglad Epidemiologiczny . 2017 . 71 . 2 . 207–219 . 28872286.

External links

• Synthesis of Oxazolidinones – Recent Literature