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

Article abstract of DOI:10.1016/j.bmcl.2008.05.071

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.