Investigating the Antibacterial Activity of Biphenylthiazoles against Methicillin- and Vancomycin-Resistant <i>Staphylococcus aureus</i> (MRSA and VRSA)

Phenylthiazoles were reported previously as a new scaffold with antibacterial activity against an array of multidrug-resistant staphylococci. However, their promising antibacterial activity was hampered in large part by their short half-life due to excessive hepatic clearance. Close inspection of the structure–activity-relationships (SARs) of the phenylthiazoles revealed two important structural features necessary for antibacterial activity (a nitrogenous and a lipophilic component). Incorporating the nitrogenous part within a pyrimidine ring resulted in analogues with a prolonged half-life, while the biphenyl moiety revealed the most potent analogue <b>1b</b>. In this study, advantageous moieties have been combined to generate a new hybrid scaffold of 5-pyrimidinyl­biphenyl­thiazole with the objective of enhancing both anti-MRSA activity and drug-like properties. Among the 37 tested biphenylthiazoles, piperazinyl-containing derivatives <b>10</b>, <b>30</b>, and <b>36</b> were the most potent analogues with MIC values as low as 0.39 μg/mL. Additionally, <b>36</b> exhibited significant improvement in stability to hepatic metabolism