Identification of quinolinyl-containing dual soluble epoxide hydrolase/fatty acid amide hydrolase inhibitors with moderate potency towards acetylcholinesterase

Using a polypharmacological approach, we designed two different quinolinyl libraries by merging the pharmacophores of three targeted enzymes, fatty acid amide hydrolase (FAAH), soluble epoxide hydrolase (sEH), and acetylcholinesterase (AChE). A 5-step synthetic scheme yielded 13 various analogs that were evaluated in FAAH, sEH, and AChE biological enzymatic assays. Most analogs are active in human FAAH and human sEH but possess only moderate activity in electric eel AChE, exemplified with <b>9i</b>, a 3-quinolinyl-4-nitrophenyl analog with 15.8 nM, 36.4 nM, and 2.165 μM inhibition potencies in FAAH, sEH, and AChE respectively. Docking studies of <b>9i</b> revealed key interactions with FAAH and sEH but limited interactions with AChE, suggesting directions for future structural modifications that could improve potency and selectivity.