In Vitro Evaluation and Docking Studies of 5-oxo-5H-furo[3,2-g]chromene-6-carbaldehyde Derivatives as Potential Anti-Alzheimer’s Agents

Abstract

A series of novel 2-carbo–substituted 5-oxo-5H-furo[3,2-g]chromene-6-carbaldehydes and their 6-(4-trifluoromethyl)phenylhydrazono derivatives have been prepared and evaluated for biological activity against the human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The most active compounds from each series were, in turn, evaluated against the following enzyme targets involved in Alzheimer’s disease, β-secretase (BACE-1) and lipoxygenase-15 (LOX-15), as well as for anti-oxidant potential. Based on the in vitro results of ChE and β-secretase inhibition, the kinetic studies were conducted to determine the mode of inhibition by these compounds. 2-(4-Methoxyphenyl)-5-oxo-5H-furo[3,2-g]chromene-6-carbaldehyde (2f), which exhibited significant inhibitory effect against all these enzymes was also evaluated for activity against the human lipoxygenase-5 (LOX-5). The experimental results were complemented with molecular docking into the active sites of these enzymes. Compound 2f was also found to be cytotoxic against the breast cancer MCF-7 cell line.

Biochemical Characterization of 13-Lipoxygenases of Arabidopsis thaliana

“…It is of note that high concentrations of substrate eliminated MJ’s activity on LOX3 when probed at inhibitor concentrations of 113 µM. This competitive characteristic was also the case for LOX6 with 12-OPDA (see Figures S8B and S9A ), suggestive of a mixed mode of enzyme inhibition [ 66 ]. The types of inhibition tentatively assessed herein might be complicated and not uniform [ 67 ], but in-depth physical chemistry analysis, as performed in Mogul et al [ 67 ], was beyond the scope of this manuscript.…”

“…Whether 12-OPDA targets C203 or other cysteinyl thiols in PLAT domain proteins should be investigated in future studies to elucidate the specificity of protein activity regulation by 12-OPDA, as demonstrated in this study for At-13-LOXs. Effective 13-LOX, hLOX12 and hLOX5 inhibitors are reported to exhibit IC 50 values below 5 µM [ 66 ], qualifying 12-OPDA as a weak LOX inhibitor. However, the potential interaction of 12-OPDA or cyclopentenones related to 12-OPDA, for example, PGJ 2 or 15d-PGJ 2 , with proteins of LOX activity, such as the LOX4-related hLOX12 (see Figure 8 ), provide novel insights and promising perspectives.…”

Recent advancements in chromone as a privileged scaffold towards the development of small molecules for neurodegenerative therapeutics

“…The authors reported compound 24 as the most potent compound of the study with IC 50 values of 5 μM, 10 μM, 14 μM, 10 μM, 15 μM, and 29 μM for AChE, BuChE, BACE1, COX-2, LOX-15, and LOX-5, respectively. Further, they reported 5-oxo-5 H -furo[3,2- g ]chromene-6-carbaldehyde derivatives 92 as potential anti-Alzheimer's agents. The study suggested that the compound 2-(4-methoxyphenyl)-5-oxo-5 H -furo[3,2- g ]chromene-6-carbaldehyde 25 was the most potent against h AChE, h BuChE, LOX-15, and LOX-5 with in vitro IC 50 values of 10 μM, 5 μM, 10 μM, and 15 μM, respectively.…”

Synthesis of New 3-Arylcoumarins Bearing N-Benzyl Triazole Moiety: Dual Lipoxygenase and Butyrylcholinesterase Inhibitors With Anti-Amyloid Aggregation and Neuroprotective Properties Against Alzheimer’s Disease

“…Such an approach can be achieved through the combination of effective pharmacophoric groups in a unique small molecule. This paradigm is more effective than one-target, one-drug concept ( Schewe, 2002 ; Oset–Gasque and Marco–Contelles, 2018 ; Jończyk et al, 2019 ; Mphahlele et al, 2019b ). Drug combination therapies for the treatment of AD lead to more beneficial therapeutic effects and resulted in the superior in vivo outcomes compared to the one-target compounds having high affinity, even if the multi-target small molecules have mild activity against one or several targets ( Morphy and Rankovic, 2007 ).…”

“…Drug combination therapies for the treatment of AD lead to more beneficial therapeutic effects and resulted in the superior in vivo outcomes compared to the one-target compounds having high affinity, even if the multi-target small molecules have mild activity against one or several targets ( Morphy and Rankovic, 2007 ). The synergy between inhibiting an enzyme and activating or blocking a receptor is the advantage achieved with the use of MTDLs ( Cai et al, 2020 ; Mphahlele et al, 2019b ; Montanari et al, 2019 ; Kashyap et al, 2020 ; Tripathi et al, 2019 ).…”