Synthesis and biological evaluation of 1-(benzenesulfonamido)-2-[5-(N-hydroxypyridin-2(1H)-one)]acetylene regioisomers: A novel class of 5-lipoxygenase inhibitors

A hitherto unknown class of linear acetylene regioisomers were designed such that a SO2NH2 group was located at the ortho-, meta-, or para-position of the acetylene C-1 phenyl ring, and a N-hydroxypyridin-2(1H)-one moiety was attached via its C-5 position to the C-2 position on an acetylene template (scaffold). All three regioisomers inhibited 5-lipoxygenase (5-LOX), where the relative potency order was 2-SO2NH2 (IC50 = 10 μM) >3-SO2NH2 (IC50 = 15 μM) >4-SO2NH2 (IC50 = 68 μM) relative to the reference drug nordihydroguaiaretic acid (NDGA; IC50 = 35 μM). The 2-SO2NH2 regioisomer (ED50 = 86.0 mg/kg po) exhibited excellent oral anti-inflammatory (AI) activity that was more potent than aspirin (ED50 = 128.9 mg/kg) and marginally less potent than ibuprofen (ED50 = 67.4 mg/kg). The N-hydroxypyridin-2(1H)one moiety provides a novel pharmacophore for the design of cyclic hydroxamic mimetics capable of chelating 5-LOX iron for exploitation in the design of 5-LOX inhibitory AI drugs.