Synthesis of new 1‐(2‐, 3‐, or 4‐methanesulfonylphenyl)‐2‐[5‐(N‐hydroxypyridin‐2(1H)‐one)]acetylene regioisomers: A search for novel cyclooxygenase and lipoxygenase inhibitors

Abstract

A group of acetylene regioisomers were designed such that a cyclooxygenase-2 (COX-2) SO 2 Me pharmacophore was located at the ortho-, meta-, or para-position of the acetylene C-1 phenyl ring, and an iron-chelating 5-lipoxygenase (5-LOX) N-hydroxypyridin-2(1H)-one moiety was attached via its C-5 position to the C-2 position on an acetylene template (scaffold). These target linear acetylene regioisomers were synthesized via a palladium-catalyzed Sonogashira cross-coupling reaction. Structure-activity data acquired using in vitro cell-based inhibition assays indicated that this novel class of 1-(2-, 3-, or 4-methanesulfonylphenyl)-2-[5-(N-hydroxypyridin-2(1H)-one)]acetylene regioisomers did not inhibit the COX-2 or (5-LOX) enzymes, and that they are devoid of in vivo anti-inflammatory activities.

Identifying Chelators for Metalloprotein Inhibitors Using a Fragment-Based Approach

“…Unlike the zinc-dependent MMPs and LF that were more effectively inhibited by the sulfur (thione) derivatives of the hydroxypyrones ( 1d-12d ) and hydroxypyridinones ( 1e-12e ), 5-LO was inhibited by both O,O and O,S chelators of these compound classes (compare 1d and 2d; 8e and 9e ). Consistent with our findings, fragment 1e has appeared in the literature as part of 5-LO inhibitors and as dual inhibitors of 5-LO and COX 66–68. Furthermore, two salicylic acid derivatives ( 6f , 9f ) were identified as 5-LO hits with compound 9f having an IC 50 value of 75 μM against 5-LO.…”