The structure–activity and structure–kinetic relationships of a new tert-butylphenylthiazole series with oxadiazole linkers were conducted with the objective of obtaining a new orally available antibacterial compounds. Twenty-two new compounds were prepared, purified and identified. Their activity against methicillin-resistant Staphylococcus aureus were examined. Compound 20 with 3-hydroxyazetidine as a nitrogenous side chain showed promising activity against twenty-four clinical isolates, including vancomycin-resistant staphylococcal and enterococcal species with MIC values ranging from 4–8 μg mL⁻¹. Additional advantages of this compound include an ability to eradicate staphylococcal biofilm mass in a dose-dependent manner as well as high metabolic stability after an oral dose of 25 mg kg⁻¹ with a biological half-life that exceeds 5 hours and a plasma concentration (C_max) that exceeds the MIC values.