The Phenylthiazole scaffold has been reported to exhibit an outstanding and promising antibacterial activity against a wide range of Gram positive multidrug-resistant bacteria, especially, staphylococci. According to the structure-activity relationship (SAR) a guanidine hydrophilic head moiety and a lipophilic tail moiety have been identified as crucial structural characteristics. In this study, the lipophilic component was investigated deeply through the synthesis of eight compounds using both direct and in situ Suzuki miyaura cross coupling reaction. Notably, compound 8d has demonstrated a promising MIC values against superbugs, including MRSA USA300, C. difficile, TolC Mutant E.coli, N. gonorrheae 181, and wild type C. albicans. These microbiological findings suggest that compound 8d holds a potential activity as an effective antibiotic against these challenging pathogens. Further research and development studies of this unique class of antibiotics possibly will lead to the discovery of new scaffolds and nucleus, hopefully used as a treatment for multidrug-resistant bacterial and fungal infections.