Synthesis of Urea‐Containing Derivatives and their Application as Potential Anti‐Methicillin‐Resistant Staphylococcus Aureus Agents

We describe the synthesis and activity against methicillin‐resistant Staphylococcus aureus (MRSA) of a collection of urea‐containing amides. The approach considered the ureido group as a bioisoster of known FabI inhibitors. NMR characterization and density functional theory studies demonstrated the presence of s‐cis and s ‐ trans rotamers in the N ‐benzyl examples (series 2 ). Preliminary screening showed the ability of series 1 and 3 ( N ‐aryl and N ‐arilpiperidone derivatives, respectively) to inhibit the bacterial growth of two MRSA strains (a clinical isolate and ATCC 33591). Compound 3b inhibited 50% of the clinical strain and 34% of the ATCC. Subsequent biological assays let us determine the IC 50 values of the most active ureas in both strains, standing out compounds 1a (45.8 ± 2.3 μM) and 3b (43.6 ± 2.0 μM). Finally, molecular docking suggests FabI as a possible molecular target for the designed compounds.