Design, Synthesis, and Molecular Docking of Some Novel Tacrine Based Cyclopentapyranopyridine‐ and Tetrahydropyranoquinoline‐Kojic Acid Derivatives as Anti‐Acetylcholinesterase Agents
Saeed Babaee, Gholamabbas Chehardoli, Tahmineh Akbarzadeh, Mohammad Ali Zolfigol, Mohammad Mahdavi, Arezoo Rastegari, Farshad Homayouni Moghadam, Zahra Najafi
Abstract
Abstract A novel series of tacrine based cyclopentapyranopyridine‐ and tetrahydropyranoquinoline‐kojic acid derivatives were designed, synthesized, and evaluated as anti‐cholinesterase agents. The chemical structures of all target compounds were characterized by 1 H‐NMR, 13 C‐NMR, and elemental analyses. The synthesized compounds mostly inhibited acetylcholinesterase enzyme (AChE) with IC 50 values of 4.18–48.71 μM rather than butyrylcholinesterase enzyme (BChE) with IC 50 values of >100 μM. Among them, cyclopentapyranopyridine‐kojic acid derivatives showed slightly better AChE inhibitory activity compared to tetrahydropyranoquinoline‐kojic acid. The compound 10‐amino‐2‐(hydroxymethyl)‐11‐(4‐isopropylphenyl)‐7,8,9,11‐tetrahydro‐4 H ‐cyclopenta[ b ]pyrano[2′,3′ : 5,6]pyrano[3,2‐ e ]pyridin‐4‐one ( 6f ) bearing 4‐isopropylphenyl moiety and cyclopentane ring exhibited the highest anti‐AChE activity with IC 50 value of 4.18 μM. The kinetic study indicated that the compound 6f acts as a mixed inhibitor and the molecular docking studies also illustrated that the compound 6f binds to both the catalytic site (CS) and peripheral anionic site (PAS) of AChE. The compound 6f showed moderate neuroprotective properties against H 2 O 2 ‐induced cytotoxicity in PC12 cells. The theoretical ADME study also predicted good drug‐likeness for the compound 6f . Based on these results, the compound 6f seems to be a very promising AChE inhibitor for the treatment of Alzheimer's disease.