Synthesis and structure-activity relationship study of tacrine-based pyrano[2,3-c]pyrazoles targeting AChE/BuChE and 15-LOX

A series of tacrine-based pyrazolo[4′,3′:5,6]pyrano[2,3-b]quinolines and related compounds were designed and synthesized for targeting AChE, BuChE and 15-LOX enzymes in the field of Alzheimer's disease therapy. Most of compounds showed potent activity against cholinesterases and mild potency toward 15-LOX enzyme. In particular, compounds 29, 32 and 40 displayed inhibition at nano-molar level against AChE and BuChE (IC50s = 0.005–0.08 μM), being more potent than reference drug tacrine. Moreover, compound 32 with IC50 value of 31 μM was the most potent compound against 15-LOX. The cytotoxicity assay on HepG2 cells revealed that compounds 29 and 32 showed no significant cytotoxic activity even at concentration of 50 μM. The cytotoxicity of compounds 29 and 32 was significantly less than that of tacrine at higher concentrations. A series of tacrine-based pyrazolo[4′,3′:5,6]pyrano[2,3-b]quinolines and related compounds were synthesized for targeting AChE, BuChE and 15-LOX without cytotoxic activity against on HepG2 cells. Most of compounds showed potent activity against cholinesterases and mild potency toward 15-LOX enzyme. [Display omitted] •Several tacrine-based compounds were synthesized as multi-target-directed ligands.•The inhibitory activity of the compounds was tested against AChE, BChE and 15-LOX.•Most of compounds showed sub-micromolar activity against cholinesterases.•Some compounds were more potent than tacrine as reference drug.•Most of compounds showed mild potency toward 15-LOX enzyme.