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Faculty of PharmacyUniversity of Medicine and Pharmacy of Tîrgu Mureş

UNIVERSITATEA DEMEDICINĂ ŞI FARMACIETÎRGU MUREŞ

Oxazolidinones: present and future

Student: Karola TolvaiCoordinator: Aura Rusu, teaching assistant, PhD

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The oxazolidinone (OXZ) class

● new class of synthetic antibiotics●active against Gram-positive bacteria, includingmethicillin- and vancomycin resistant staphylococci, vancomycin-resistant enterococci, penicillin-resistant pneumococci●approved representative - linezolid

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Physical properties of OXZ

●Color/Form: White crystals from ethyl acetate and hexanes●Melting Point: 181.5-182.5 °C●Water solubility : 3mg/ml●Two crystal modifications (polymorphs)

Polymorphs Melting point (°C)

Form I 181

Form II 155

● in some articles there are described three polymorphs

Ref:• https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=441401&loc=ec_rcs• http://www.drugbank.ca/drugs/DB00601• Dhaval Joshipura et al - Crystal forms of linezolid, Der Pharmacia Lettre, 2013, 5 (1):279-284

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Synthesis methods

1. Chiral resolution method

2. Iodocyclocarbamation

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3. Using urea and ethanolamine

Synthesis methods

4. Nickel catalyzed cycloaddition

Ref: Pandit N et al- Current Updates on Oxazolidinone and Its Significance, International Journal of Medicinal Chemistry, 2012, 1-24

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Structure activity relationship (SAR)

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Mechanism of action

It selectively inhibits bacterial protein synthesis through binding to sites on the bacterial ribosome and prevents the formation of a functional 70S-initiation complex, compared to aminoglycosides and macrolides, which inhibit the ribosomal protein synthesis.

Ref: • Pandit N et al - Current Updates on Oxazolidinone and Its Significance, International Journal of Medicinal

Chemistry, 2012, 1-24

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2 . Anticoagulant activity3. Antitubercular activity4. Antidepressant or psychotropic activity5. Phospholipase inhibitor6. CNS depressant7. Centrally acting muscle relaxants8. Antithyroid agents9. Antiblasting activity in chemotherapy (=retardation of growth)10. Use in urinary tract infection11. Agriculture fungicide (Famoxadone)

Ref: Pandit N et al - Current Updates on Oxazolidinone and Its Significance, International Journal of Medicinal Chemistry, 2012, 1-24

Pharmacological Effects of OXZ

1. Antibacterial activity

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● the treatment of community-acquired and nosocomial pneumonia ● complicated and uncomplicated skin and soft-tissue infections● infections caused by MRSA and VRE● recently approved for use in children● for the management of diabetic foot infections

Ref: Vara Prasad JVN– New oxazolidinones, Current Opinion in Microbiology, 2007, 10:454–460

Linezolid

Representative

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ANM approved linezolid as Zyvoxid or Linezolid under the following formulations: ● tablets (400 and 600 mg )● perfusion (2 mg/ml )● granules for oral suspension (100mg/5 ml )

In Romania:

Representative:

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Absorption. It is rapidly and extensively absorbed after oral dosing. Maximum plasma concentrations are reached approximately 1 to 2 hours after dosing, and the absolute bioavailability is approximately 100%.

Toxicity. Clinical signs of acute toxicity lead to decreased activity, ataxia, vomiting and tremors.

Ref: Pandit N et al - Current Updates on Oxazolidinone and Its Significance, International Journal of Medicinal Chemistry, 2012, 1-24

Pharmacokinetic Parameters of linezolid

Protein Binding. 31%. Biotransformation. It is primarily metabolized by oxidation of the morpholine ring Half-Life. 4,5–5,5 hours. Excretion. Renal and fecal

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Side effects of linezolid

In clinical trial - DRAE(max. 28 days of

treatment)

Post marketing studies(>28 days)

GastrointestinalNauseaDiarrheaHeadacheTaste alterationVaginal candidiasisDizzinessInsomnia, fatigue

Neuropathy (peripheral and ocular)Myelosupression (anemia, thrombocytopenia)

Ref: Donald C. Vinh, Ethan Rubinstein - Linezolid a review of safety and tolerability, Journal of Infection, 2009, 59(S1), S59 S74

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Radezolid (RX-1741) has recently completed two Phase II clinical trials: one for community acquired pneumonia and the second for uncomplicated skin and skin structure infections.

Ref: Pandit N et al - Current Updates on Oxazolidinone and Its Significance, International Journal of Medicinal Chemistry, 2012, 1-24

Other OXZ derivatives

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Other OXZ derivatives

YC-20 : The activity of YC-20 is slightly superior to linezolid

Ref: Pandit N et al - Current Updates on Oxazolidinone and Its Significance, International Journal of Medicinal Chemistry, 2012, 1-24

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Torezolid (TR-700) and Torezolid phosphate (TR-701) – phase III- tolerability of torezolid phosphate is similar to that observed with linezolid- showed favorable results in the treatment of ABSSSI (Acute Bacterial Skin and Skin Structure Infections) in the first phase III clinical trial

Other OXZ derivatives

Ref: Pandit N et al - Current Updates on Oxazolidinone and Its Significance, International Journal of Medicinal Chemistry, 2012, 1-24 Oniga O et al – Chimia si actiunea antibioticelor antibacteriene, Editura medicala “Iuliu Hatieganu”, Cluj-Napoca, 2013, 186-189

The advantages of torezolid compared to linezolid: the administration of only one dose per day, activity on some atypical bacteria, such as Legionella and Chlamydia sp., bacterial resistance is developed slower and reduced myelosuppresion.

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Posizolid (AZD2563) : - bioavailability was reported to be dose related (food increases it at all doses)

Ref: Karen Joy Shaw and Michael R. Barbachyn - The oxazolidinones: past, present, and future, Ann. N.Y. Acad. Sci., 2011, 1241: 48–70Oniga O et al – Chimia si actiunea antibioticelor antibacteriene, Editura medicala “Iuliu Hatieganu”, Cluj-Napoca, 2013, 186-189

Other OXZ derivatives

- at a concentration of 2 mg/ml it proved inhibitory capacity for over 98% of Gram positive bacterial strains

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Eperezolid: - was not advanced to Phase III studies – short T- almost identical to linezolid in preclinical profiles including solubility, antimicrobial potency and spectrum of activity, lower pKa - requires a larger dose and has bone marrow toxicity

Other OXZ derivatives

Ref:• Jie Jack Li, E. J. Corey - Drug Discovery: Practices, Processes, and Perspectives, John Wiley & Sons,

New Jersey, 2013;• Karen Joy Shaw and Michael R. Barbachyn - The oxazolidinones: past, present, and future, Ann. N.Y. Acad. Sci.,

2011, 1241: 48–70.

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Oxazolidinone derivates with other biological activities

Rivaroxaban (BAY-59-7939)

Phase III anticoagulant activity

- deep vein thrombosis or pulmonary embolism

Sutezolid

(PNU-100480)

Ongoing phase II

antitubercular activity

- potential to significantly shorten the duration of therapy for drug-susceptible as well as multidrug-resistant tuberculosis.

Toloxatone Phase I antidepressant activity

- extensively metabolized

Ref: • Villemagne B et al - Tuberculosis: The drug development pipeline at a glance, European Journal of

Medicinal Chemistry, 2012, 51: 1-16; • Karen Joy Shaw and Michael R. Barbachyn - The oxazolidinones: past, present, and future, Ann.

N.Y. Acad. Sci., 2011, 1241: 48–70

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Hybrid oxazolidinones

The most advanced oxazolidinone and quinolone hybrid, ACT-179811 (Cadazolid) is currently recruiting participants into a Phase II clinical trial for the treatment of Clostridium difficile infections.

It seems that the combination of different drugs with different pharmacophors in one structure will be an interesting option to overcome the intrinsic resistance of most Gram-negative bacteria to oxazolidinones.

Ref: Katarzyna M et al - Recent development of potent analogues of oxazolidinone antibacterial agents, Bioorganic & Medicinal Chemistry, 2013, 21:577–591

Quinolone moiety

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The construction of an oxazolidinone ring in mefloquine’s structure can enhance the activity against M. tuberculosis. Advanced studies revealed that a dimethoxy derivative exhibits superior potency (anti-tubercular activity).

Ref: Katarzyna M et al - Recent development of potent analogues of oxazolidinone antibacterial agents, Bioorganic & Medicinal Chemistry, 2013, 21:577–591

Hybrid oxazolidinones

Mefloquine

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A hybrid biarylooxazolidinones - demonstrated both superior translation and bacterial inhibition when compared to linezolid.

Ref: Katarzyna M et al - Recent development of potent analogues of oxazolidinone antibacterial agents, Bioorganic & Medicinal Chemistry, 2013, 21:577–591

Hybrid oxazolidinones

biaryl

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Nitroimidazolyl-oxazolidinone hybrids - potency at non-cytotoxic concentration.

Ref: Katarzyna M et al - Recent development of potent analogues of oxazolidinone antibacterial agents, Bioorganic & Medicinal Chemistry, 2013, 21:577–591

Hybrid oxazolidinones

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Conclusions

● it’s an original class due to it’s special mechanism of action

● although only linezolid is known, numerous other molecules are still in development

● besides the antibacterial effect, they have other promising useful pharmacological effects

● it is possible to raise the number of representative compounds

● there is a continues need for new antibacterial molecules because of the increase in bacterial resistance to antibiotics

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Thank you for your attention!