Synthesis and Biological Evaluation of Coumarin Triazoles as Dual Inhibitors of Cholinesterases and β-Secretase

Abstract

Coumarin is a naturally occurring bioactive pharmacophore with wide occurrence among central nervous system (CNS)-active small molecules. 8-Acetylcoumarin, one of the natural coumarins, is a mild inhibitor of cholinesterases and β-secretase, which are vital targets of Alzheimer’s disease. Herein, we synthesized a series of coumarin–triazole hybrids as potential multitargeted drug ligands (MTDLs) with better activity profiles. The coumarin–triazole hybrids occupy the cholinesterase active site gorge from the peripheral to the catalytic anionic site. The most active analogue, 10b, belonging to the 8-acetylcoumarin core, inhibits acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-secretase-1 (BACE-1) with IC50 values of 2.57, 3.26, and 10.65 μM, respectively. The hybrid, 10b, crosses the blood–brain barrier via passive diffusion and inhibits the self-aggregation of amyloid-β monomers. The molecular dynamic simulation study reveals the strong interaction of 10b with three enzymes and forming stable complexes. Overall, the results warrant a detailed preclinical investigation of the coumarin–triazole hybrids.

Recent Trends in the Synthesis and Bioactivity of Coumarin, Coumarin–Chalcone, and Coumarin–Triazole Molecular Hybrids

“…A series of coumarin−triazole hybrid syntheses conducted by Sharma and Bharate (2023) relied on the propargylation of 8-acetyl-coumarin 193 with propargyl bromide to give compound 194 ( Scheme 44 ) [ 111 ]. The click reaction of the propargyl 194 with benzyl bromide 195 in the presence of sodium azide yielded the corresponding coumarin−triazole hybrids 196a – d in medium yields.…”

“…The coumarin–triazole hybrids developed by Sharma and Bharate (2023) [ 111 ] were screened for their inhibition of ChEs and BACE-1. The most active compound, 196b ( Scheme 44 , Figure 9 ), inhibited acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-secretase-1 (BACE-1) with IC 50 values of 2.57, 3.26, and 10.65 μM, respectively.…”

“…Scheme 44. Synthesis of coumarin-triazoles 196a-d from 8-acetyl-coumarin 193[111] Pingaew et al (2014). synthesized novel coumarin-triazole-chalcone hybrids in three steps (Scheme 45)[112].…”

“…Coumarin-based compounds as anti-cholinesterase.The coumarin-triazole hybrids developed by De Sousa et al (2021) were also evaluated for anti-cholinesterase activity via the inhibition of acetylcholinesterase[105]. Compound 169 (Scheme 38, Figure9) showed an inhibitory activity of 17.25 ± 1.56% at 50 µmol/L.The coumarin-triazole hybrids developed by Sharma and Bharate (2023)[111] were screened for their inhibition of ChEs and BACE-1. The most active compound, 196b (Scheme 44, Figure9), inhibited acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-secretase-1 (BACE-1) with IC 50 values of 2.57, 3.26, and 10.65 µM, respectively.…”

Coumarin Derivatives: Mechanistic Insights and Promising Applications as Potential Alzheimer's Disease (AD) Therapeutic Agents

“…Ankita et al [40] reported a number of coumarin‐triazole hybrids ( 92 – 95 ) (Figure 22) in order to design new multitargeted therapeutic ligands with enhanced activity profiles. The coumarin‐triazole hybrids reside a gorge between the catalytic anionic site and the periphery of the cholinesterase active sites.…”