Gonzalez_2026_Results.Chem_23_103159

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 9i, a 3-quinolinyl-4-nitrophenyl analog with 15.8 nM, 36.4 nM, and 2.165 microM inhibition potencies in FAAH, sEH, and AChE respectively. Docking studies of 9i revealed key interactions with FAAH and sEH but limited interactions with AChE, suggesting directions for future structural modifications that could improve potency and selectivity.