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 IC₅₀ 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.