Antibiotic resistance is a growing global health threat and requires extensive research to combat this urgent problem. Phenylthiazoles, known for their diverse biological activities including anthelmintic, insecticidal, and antimicrobial properties, have recently gained particular attention as potential anti-MRSA lead compounds. This class of compounds is an established pharmacophore for the development of new antibacterial agents, particularly against multidrug-resistant bacteria such as MRSA, a notorious pathogen resistant to most first-line antibiotics. In-depth structure-activity relationship (SAR) studies of phenylthiazoles revealed two key features critical to their antibacterial activity: a nitrogen-containing head and a lipophilic tail. In this study, we aimed to reduce the lipophilicity of phenylthiazoles and improve their overall physicochemical and pharmacokinetic profiles by synthesizing a new series bearing primary amines at the phenyl-4 position. Notably, compounds 5m exhibited bactericidal activity against MRSA, exhibiting a minimum inhibitory concentration (MIC) of only 8 µg/mL against the prevalent MRSA strain USA300.