A hitherto unknown class of linear acetylene regioisomers were designed such that a SO 2Me or SO 2NH 2 group was located at the ortho-, meta- or para-position of the acetylene C-1 phenyl ring, and a N-difluoromethyl-1,2-dihydropyridin-2-one moiety was attached via its C-5 position to the C-2 position on an acetylene template (scaffold). All three SO 2Me regioisomers, and the 4-SO 2NH 2 analog, were potent inhibitors of 5-lipoxygenase (5-LOX IC 50 = 3.2–3.5 μM range) relative to the reference drug caffeic acid (IC 50 = 4.0 μM). The SO 2Me regioisomers exhibited weak cyclooxygenease-1 (COX-1) and -2 (COX-2) inhibitory activity with a modest COX-2 selectivity index. The most potent 3-SO 2Me, 4-SO 2Me and 4-SO 2NH 2 compounds, with respective ED 50 values of 66.1, 68.5 and 86.5 mg/kg po, exhibited comparable oral anti-inflammatory (AI) activity to that of the reference drug ibuprofen (ED 50 = 67.4 mg/kg po). The N-difluoromethyl-1,2-dihydropyridin-2-one moiety provides a novel pharmacophore for the design of cyclic hydroxamic mimetics capable of inhibiting 5-LOX for exploitation in the development of 5-LOX inhibitory AI drugs.