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 microM) >3-SO(2)NH(2) (IC(50)=15 microM) >4-SO(2)NH(2) (IC(50)=68 microM) relative to the reference drug nordihydroguaiaretic acid (NDGA; IC(50)=35 microM). The 2-SO(2)NH(2) regioisomer (ED(50)=86.0mg/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.
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alta., Canada T6G 2N8.
Morshed Alam
MA
Chowdhury
Hua
H
Chen
Khaled R A
KR
Abdellatif
Ying
Y
Dong
Kenneth C
KC
Petruk
Edward E
EE
Knaus
D000114:Acetylene / Q000138:chemical synthesis* / Q000737:chemistry; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001094:Arachidonate 5-Lipoxygenase / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004487:Edema / Q000188:drug therapy; D020128:Inhibitory Concentration 50; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D009637:Masoprocol / Q000737:chemistry; D008956:Models, Chemical; D011725:Pyridines / Q000737:chemistry; D051381:Rats; D013237:Stereoisomerism
D000893:Anti-Inflammatory Agents; D016859:Lipoxygenase Inhibitors; D011725:Pyridines; D009637:Masoprocol; D001094:Arachidonate 5-Lipoxygenase; D000114:Acetylene