Oxazolidinones are antibacterial agents active against Gram-positive bacteria. Studies have shown that optionally varied C-5 substituted oxazolidinones resulted in derivatives with comparable or enhanced antibacterial activity in comparison to linezolid. Oxazolidinones are also plagued with unwanted monoamine oxidase (MAO) inhibition as side-effect, due to structural similarity with MAO inhibitors, namely, toloxatone. In this study, we synthesized  optionally varied C-5 hydroxamic acid containing oxazolidinones and investigated their antibacterial and MAO inhibitory activities.Susceptibility testing of the compounds was performed by agar dilution method with discs containing 30 �g/mL test compounds and the diameter zone of inhibition (mm) measured. Computer model interactions of representative oxazolidinones at the bacterial ribosomal receptor site was performed using Molecular Operating Environment (MOE v 2012.10) software. MAO-A or -B inhibition was determined in 96 well microtiter plates using tyramine as a mixed substrate for MAO-A and -B. Blanks containing buffer instead of tyramine and controls containing distilled water instead of test compounds, were run parallel to the samples in a SunriseTM microplate absorbance reader at 498nm every minute for 10 minutes, then every 10 minutes for 20 minutes and every 20 minutes until 90 minutes.The oxazolidinone hydroxamates and their N-carbamate precursors were devoid of antibacterial activity. Computer modeling suggested that this lack of activity could be due to disruption of hydrogen bond formation between the hydroxamate N-OH moiety and the 5'-phosphate of G2540, as a result of steric overlap of the two oxygen atoms due to their proximity (~1.5 �). However, the compounds showed weak to moderate MAO-A and -B inhibitions at 50 and 200 �M concentrations. MAO inhibitions ranged from 0 to 68.8% for both isoenzymes. This study showed that the presence of a hydroxamic acid functional group at the C-5 position of the oxazolidinone ring is detrimental to antibacterial and MAO inhibitory activities.Supported by KURA Grant # PC01/09 (OAP), GS 01/01, GS 01/03 & GS 01/05 (SAF)

Novel oxazolidinone hydroxamic acid derivatives: Synthesis and biological evaluation

248th National Meeting (2014)

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