Design, synthesis and docking study of novel coumarin ligands as potential selective acetylcholinesterase inhibitors

Abstract

New coumaryl-thiazole derivatives with the acetamide moiety as a linker between the alkyl chains and/or the heterocycle nucleus were synthesized and in vitro tested as acetylcholinesterase (AChE) inhibitors. 2-(diethylamino)-N-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)acetamide (6c, IC50 value of 43 nM) was the best AChE inhibitor with a selectivity index of 4151.16 over BuChE. Kinetic study of AChE inhibition revealed that 6c was a mixed-type inhibitor. Moreover, the result of H4IIE hepatoma cell toxicity assay for 6c showed negligible cell death. Molecular docking studies were also carried out to clarify the inhibition mode of the more active compounds. Best pose of compound 6c is positioned into the active site with the coumarin ring wedged between the residues of the CAS and catalytic triad of AChE. In addition, the coumarin ring is anchored into the gorge of the enzyme by H-bond with Tyr130.

Design, Synthesis, In Vitro Evaluation and Docking Studies of Pyrazole‐Thiazole Hybrids as Antimicrobial and Antibiofilm Agents

“…Among the aforementioned scaffolds, coumarin and thiazole have gained much attention in recent decades in the field of medicinal chemistry as leading pharmacophores with a wide range of pharmacological activities. Some of the biological properties include antioxidant, anticholinesterase activity (AChE and BuChE), carbonic anhydrase I, II, and IX inhibiting activities and aflatoxigenic activity …”

Discovery of novel dual-active 3-(4-(dimethylamino)phenyl)-7-aminoalcoxy-coumarin as potent and selective acetylcholinesterase inhibitor and antioxidant

“…The design of the novel alkylamino-coumarin derivatives (Scheme 1) was based on the structural requirements for mixed-type selective AChE inhibition present in alkylamino-indanone inhibitor recently described 13 , as well as on the widespread use of coumarins for this pharmacological activity 22 , 23 . The coumarin series was based on: 1- the maintenance of the cyclic alkylamino group, which is responsible for the interaction with the cationic catalytic site (CAS) of AChE, exploring different lengths of methylene linkers (2–6); 2-exchange of the indanone nucleus by the coumarin through non-classical isosterism of ring expansion 24 ; 3- use of hydrophobic groups at position 3 of coumarin, targeting interactions with the peripheral anionic site (PAS) of AChE.…”

Natural products and their derivatives as multifunctional ligands against Alzheimer's disease

“…A series of the novel coumarin-thiazole hybrid was synthesized in which the linker between the N-alkyl chains and heterocyclic core is the acetamide moiety. Among this series, compound 10i is a potent mixed-type inhibitor of AChE (IC 50 value 43 nM) (Sonmez et al, 2017).…”