Synthesis and structure-activity relationships of novel 5-(hydroxamic acid)methyl oxazolidinone derivatives as 5-lipoxygenase inhibitors

Abstract

Oxazolidinone hydroxamic acid derivatives were synthesised and evaluated for inhibitory activity against leukotriene (LT) biosynthesis in three in vitro cell-based test systems and on direct inhibition of recombinant human 5-lipoxygenase (5-LO). Thirteen of the 19 compounds synthesised were considered active ((50% inhibitory concentration (IC₅₀) ≤ 10 µM in two or more test systems)). Increasing alkyl chain length on the hydroxamic acid moiety enhanced activity and morpholinyl-containing derivatives were more active than N-acetyl-piperizinyl derivatives. The IC₅₀ values in cell-based assay systems were comparable to those obtained by direct inhibition of 5-LO activity, confirming that the compounds are direct inhibitors of 5-LO. Particularly, compounds PH-249 and PH-251 had outstanding potencies (IC₅₀ < 1 µM), comparable to that of the prototype 5-LO inhibitor, zileuton. Pronounced in vivo activity was demonstrated in zymosan-induced peritonitis in mice. These novel oxazolidinone hydroxamic acid derivatives are, therefore, potent 5-LO inhibitors with potential application as anti-allergic and anti-inflammatory agents.

Keywords:

• Hydroxamic acid derivatives
• oxazolidinone-hydroxamates
• 5-lipoxygenase inhibitors
• leukotrienes

Acknowledgements

The authors acknowledge the HSC Animal Resources Centre for assistance with research equipment and animals. The authors are also grateful to Ms. Elizabeth Philip, for her excellent technical assistance.

Ethical approval statement

Experiments involving living animals and their care were performed in strict compliance with the Regulations for the Use of Laboratory Animals in the Health Sciences Centre, Kuwait University, and complied with the National Institute of Health guide for the care and use of laboratory animals (NIH Publication # 8023, revised 1978). The protocol was approved by the Health Sciences Centre Animal Experimentation Ethical Committee of Kuwait University. All efforts were made to minimise the animal’s suffering and to reduce the number of animals used.

All experiments involving human blood were conducted with ethical approval from the Health Sciences Centre Ethical Committee of Kuwait University and carried out in accordance with the “Declaration of Helsinki” for experiments involving human subjects. All donors gave informed consent.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This study was supported by Kuwait University (KU) Research Sector Grant [MR01/14]; KU, HSC OMICS Research Unit Grant [GM01/15]; KU General Facilities Science (GF-S), Faculty of Science Grants [GS01/03, GS01/05, and GS02/10].