Novel 1,2,4-oxadiazole oxazolidinone compounds active as antibacterial agents



Use and misuse of antibacterial agents have resulted in the development of bacterial resistance to all antibiotics in clinical use irrespective of the chemical class or molecular target of the drug. Infections caused by multiresistant Gram-positive cocci, such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and penicillin-resistant Streptococcus pneumoniae (PNSSP), have emerged as major public health concern, both in hospital and community settings worldwide. The need for new antibiotics urged the Infectious Disease Society of America (IDSA) to issue the challenge to develop ten new antibiotics by 2020.
Oxazolidinones are a class of antibacterial agents which displayed activity against a variety of Gram-positive pathogens and are highly potent against multidrug-resistant bacteria. In particular, oxazolidinones are used to treat skin and respiratory tract infections caused by Staphylococcus aureus and streptococci strains, as well as being active against vancomycin-resistant Enterococcus faecium. Linezolid (Figure 1), the first oxazolidinone antibiotic approved for clinical use, has been shown to inhibit translation at the initiation phase of protein synthesis in bacteria by binding to the 50S ribosomal subunit. Since 2001, however, linezolid resistance began to appear in Staphylococcus aureus and Enterococcus faecium clinical isolates and the rate of resistance raised especially among enterococci and Staphylococcus epidermidis strains with its usage.[1-4] In addition, linezolid therapy is not without side effects such as reversible myelosuppression and inhibition of monoamine oxidases (MAO).
In this context, many researchers have attempted to modify, without even obtaining results such as to lead to approval for use of new molecules, the structure of linezolid to improve the antibacterial activity. In order to rationalize the site of modifications, the structure of linezolid can formally be divided into four portions according to oxazolidinone antibacterials nomenclature[5]: i) the A-ring, consisting of the oxazolidinone central heterocycle; ii) the B-ring, consisting of a N-aryl moiety linked to the oxazolidinone nitrogen; iii) the C-ring, consisting of a carbo-heterocyclic functional group, not necessarily aromatic; iv) the side-chain, consisting of any functional group linked to the oxazolidinone C(5) or in an isosteric position with respect to an A-ring of general type (Figure 1).



The present invention is based on the discovery that the substitution of the C-ring of linezolid-like molecules, with a five-membered heterocyclic ring, also substituted, containing 2 or 3 heteroatoms, is effective for the obtainment of new antibiotic oxazolidinones with a tunable activity by the presence of further modifications at the B-ring and at the C(5) side-chain of the oxazolidinone nucleus.
Therefore, the object of the present invention are new compounds with a general formula (I), and their use for the treatment of infections caused by Gram-positive bacteria,


as racemic mixtures or pure enantiomers or mixtures enriched with either one of the S or R enantiomer.

Therapeutic Applications
The claimed compounds are new antibiotics intended for use in the treatment of infections caused by bacteria, essentially by Gram-positive extremely resistant bacteria. For example, but not limited to, Staphylococcus spp, Enterococcus spp, Streptococcus spp, in particular in the treatment of infections caused by Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecium, Enterococcus faecalis, Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis. The compounds of the invention have proved to be active also on bacteria resistant to other antibiotics or resistant to the reference compound linezolid. Advantageously, the compounds of the invention are effective even against bacteria resistant to more than one antibiotic, against multi-resistant bacteria, for example to two or more antibiotics selected from methicillin, vancomycin, penicillin, macrolides, fluoroquinolones or linezolid.
Furthermore, the novel compounds of the invention combine the inhibitory activity or bactericidal against bacteria both susceptible or (multi)resistant to known antibiotics to a entirely acceptable toxicity or even less than that of the reference compound linezolid, thus offering an entirely beneficial clinical/therapeutic profile.



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