Atherosclerosis is a chronic inflammatory disease of the arteries that is highly prevalent in the current community. The current pharmacological treatment of atherosclerosis mainly focuses on reducing the cholesterol level of the patients but pays minimal attention to the inflammatory reactions in atherosclerosis. Past studies indicated that 5-LO contributes significantly to atherosclerosis by causing vascular alteration, monocyte recruitment, fibrous cap formation, and plaque instability. Hence, 5-LO is targeted to be inhibited to improve atherosclerosis. However, the discovery and development of most 5-LO inhibitors were hindered by poor pharmacodynamic and pharmacokinetic profiles. The main objectives of this study are to design and synthesise potent 5-LO inhibitors via hybridising the common pharmacophores of the reported 5-LO inhibitors and evaluate their 5-LO inhibitory effects in vitro. In this study, a total of 13 hybrid compounds were designed. They were successfully synthesised and characterised based on Hantzsch thiazole synthesis. These hybrid compounds were further tested for 5-LO pathway inhibition activities in cell-free and cell-based assays. The cell-free 5-LO activity inhibition assay indicated that the 3-((4-phenylthiazol-2-yl)amino)benzamide (PTBM) hybrid series tends to inhibit 5-LO activities. PTBM04 was found to be a 5-LO competitive inhibitor, and PTBM01, PTBM02, PTBM03 and PTBM06 are 5-LO non-competitive inhibitors. In the cell-based assay, PTBM04 downregulated the gene expression of LTA4H and LTC4S, whereas PTBM02 and PTBM06 downregulated the gene expression of LTC4S only. Molecular dynamics results predicted that PTBM04 inhibits 5-LO via chelating the ferrous ion while PTBM01, PTBM02, PTBM03 and PTBM06 bind to the allosteric site of 5-LO and deactivate 5-LO activities. In the pharmacokinetics aspect, these hybrid molecules were estimated to possess excellent drug-like properties.