Compounds with high lipophilic properties are often associated with bad physicochemical properties, triggering many off-targets, and less likely to pass clinical trials. Two metabolically stable phenylthiazole antibiotic scaffolds having notable high lipophilic characters, one with alkoxy side chain and the other one with alkynyl moiety, were derivatized by inserting a cyclic amine at the lipophilic tail with the objective of improving physicochemical properties and the overall pharmacokinetic behavior. Only alkynyl derivatives with 4- or 5-membered rings showed remarkable antibacterial activity. The azetidine-containing compound 8 was the most effective and it revealed a potent antibacterial effect against 15 multi-drug resistant (MDR)-Gram positive pathogens including Staphylococcus aureus, Streptococcus pneumoniae, Staphylococcus epidermidis and enterococci. Compound 8 was also highly effective in clearing 99.7% of the intracellular methicillin-resistant S. aureus (MRSA) harbored inside macrophages. In addition to the remarkable enhancement in aqueous solubility, the in vivo pharmacokinetic study in rats indicated that compound 8 can penetrate gut cells and reach plasma at a therapeutic concentration within 15 min and maintain effective plasma concentration for around 12 h. Interestingly, the main potential metabolite (compound 9) was also active as an antibacterial agent with potent antibiofilm activity.