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 SO(2)NH(2) 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-SO(2)NH(2) (IC(50) = 10 mu M) > 3-SO(2)NH(2) (IC(50) = 15 mu M) > 4-SO(2)NH(2) (IC(50) = 68 mu M) relative to the reference drug nordihydroguaiaretic acid (NDGA; IC(50) = 35 mu M). The 2-SO(2)NH(2) regioisomer (ED(50) = 86.0 mg/kg po) exhibited excellent oral anti-inflammatory (AI) activity that was more potent than aspirin (ED(50) = 128.9 mg/kg) and marginally less potent than ibuprofen (ED(50) = 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. (C) 2008 Elsevier Ltd. All rights reserved.