Design, synthesis, and evaluation of 3,7-substituted coumarin derivatives as multifunctional Alzheimer’s disease agents

Abstract

Multitarget directed ligands (MTDLs) are emerging as promising treatment options for Alzheimer's disease (AD). Coumarin derivatives serve as a good starting point for designing MTDLs due to their inherent inhibition of monoamine oxidase (MAO) and cholinesterase enzymes, which are complicit in AD's complex pathophysiology. A preliminary series of 3,7-substituted coumarin derivatives were synthesised and evaluated for enzyme inhibitory activity, cytotoxicity as well as neuroprotective ability. The results indicated that the compounds are weak cholinesterase inhibitors with five compounds demonstrating relatively potent inhibition and selectivity towards MAO-B with IC 50 values between 0.014 and 0.498 hx00B5;mM. Significant neuroprotective effects towards MPP þ -compromised SH-SY5Y neuroblastoma cells were also observed, with no inherent cytotoxicity at 10 mM for all compounds. The overall results demonstrated that substitution of the phenylethyloxy moiety at the 7-position imparted superior general activity to the derivatives, with the propargylamine substitution at the 3-position, in particular, displaying the best MAO-B selectivity and neuroprotection.

2-Aminobenzoxazole-appended coumarins as potent and selective inhibitors of tumour-associated carbonic anhydrases

“…Coumarins are considered as a privileged structure in medicinal chemistry 21 , exhibiting a plethora of bioactivities 22 , such as antioxidant 23 , anti-inflammatory 24 , antimicrobial 25 , anti-Alzheimer’s 26 , 27 , or antiproliferative 28 , 29 properties. Conjugation of coumarins with a second pharmacophore is currently gaining attention to access multitarget drugs 30 .…”

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

“…Mzezewa et al (2021) initiated the synthesis of 3,7-substituted coumarin with a Pechmann condensation of dihydroxybenzaldehyde 46 to give compound 47 , which, upon esterification with 2-bromoethylbenzene, gave 48 ( Scheme 11 ) [ 78 ]. The subsequent bromination of 48 with N -bromosuccinimide gave 49 which, upon reaction with propargylamine, gave coumarin 50 .…”

An overview of structure-based activity outcomes of pyran derivatives against Alzheimer’s disease

“…According to the findings, the propargylamine substitution at the 3-position had the most MAO-B selectivity as well as the most neuroprotective effects. In general, the findings demonstrated that the phenylethyloxy moiety being substituted at the 7-position conferred greater overall activity to the derivatives ( Mzezewa et al, 2021 ).Three novel pyrazoles containing derivatives of brominated 4-methyl 7-hydroxycoumarin were developed. The affinity of compound (5) for the crystallographic structure (4EY7) of the acetylcholine esterase enzyme was high.…”

“… ( Zare-Akbari et al, 2022 ) 2 EC 50 : 14 μM (Aβ aggregation inhibition in Tau cell model) Diethyl amino phenyl separated by 2 carbons from coumarin and a carbonyl group increased activity ( Chiu et al, 2021 ) 3 0.029 µM (Ellman assay) Substitution of phenylethyloxy at the 7-position and propargylamine at the 3-position increased activity. ( Mzezewa et al, 2021 ) 4 0.101 µM (Ellman assay) Potential activity observed due to the inclusion of the propargylamine functional group ( Mzezewa et al, 2021 ) 5 human MAO-B IC 50 = 3.9 nM human MAO-B IC 50 = 4.4 nM (acetylcholine esterase inhibition assay) Substitution of pyrazole on coumarins may show an increase in anti- Alzheimer’s activity ( Narayanan et al, 2021 ) 6 SH-SY5Y cell model The ethoxycarbonyl group increases activity ( Huang et al, 2021 ) 7 Phenyl separated from coumarin by ethylcarbonyl group imparts increased activity ( Huang et al, 2021 ) 8 Ellman assay, FRET assay) The thioxo group and ether linkage increase activity. ( Kumar et al, 2020 ) 9 Ellman assay, FRET assay ( Kumar et al, 2020 ) 10 21.71 μM (Ellman assay) Difluorobenzyl and triazole dimethylamino groups increased activity ( Karimi Askarani et al, 2020 ) 11 2.0 nM (Ellman assay) The choline-binding site was comprised of ...…”