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.
A series of multi-target directed edaravone derivatives bearing N-benzyl pyridinium moieties were designed and synthesised. Edaravone is a potent antioxidant with significant neuroprotective effects and N-benzyl pyridinium has previously exhibited positive results as part of a dual-site binding, peripheral anionic site (PAS) and catalytic anionic site (CAS), acetylcholinesterase (AChE) inhibitor. The designed edaravone-N-benzyl pyridinium hybrid compounds were docked within the AChE active site. The results indicated interactions with conserved amino acids (Trp279 in PAS and Trp84 in CAS), suggesting good dualsite inhibitory activity. Significant in vitro AChE inhibitory activities were observed for selected compounds (IC 50 : 1.2-4.6 mM) with limited butyrylcholinesterase inhibitory activity (IC 50 's >160 mM), indicating excellent selectivity towards AChE (SI: 46->278). The compounds also showed considerable antioxidant ability, similar to edaravone. In silico studies indicated that these compounds should cross the blood-brain barrier, making them promising lead molecules in the development of anti-Alzheimer's agents.
The solid-state structural analysis and docking studies of three adamantane-linked 1,2,4-triazole derivatives are presented. Crystal structure analyses revealed that compound 2 crystallizes in the triclinic P-1 space group, while compounds 1 and 3 crystallize in the same monoclinic P21/c space group. Since the only difference between them is the para substitution on the aryl group, the electronic nature of these NO2 and halogen groups seems to have no influence over the formation of the solid. However, a probable correlation with the size of the groups is not discarded due to the similar intermolecular disposition between the NO2/Cl substituted molecules. Despite the similarities, CE-B3LYP energy model calculations show that pairwise interaction energies vary between them, and therefore the total packing energy is affected. HOMO-LUMO calculated energies show that the NO2 group influences the reactivity properties characterizing the molecule as soft and with the best disposition to accept electrons. Further, in silico studies predicted that the compounds might be able to inhibit the 11β-HSD1 enzyme, which is implicated in obesity and diabetes. Self- and cross-docking experiments revealed that a number of non-native 11β-HSD1 inhibitors were able to accurately dock within the 11β-HSD1 X-ray structure 4C7J. The molecular docking of the adamantane-linked 1,2,4-triazoles have similar predicted binding affinity scores compared to the 4C7J native ligand 4YQ. However, they were unable to form interactions with key active site residues. Based on these docking results, a series of potentially improved compounds were designed using computer aided drug design tools. The docking results of the new compounds showed similar predicted 11β-HSD1 binding affinity scores as well as interactions to a known potent 11β-HSD1 inhibitor.
Structural analysis and docking studies of three adamantane-linked 1,2,4-triazole N-Mannich bases (1–3) are presented. Compounds 1, 2 and 3 crystallized in the monoclinic P21/c, P21 and P21/n space groups, respectively. Crystal packing of 1 was stabilized by intermolecular C‒H···O interactions, whereas compounds 2 and 3 were stabilized through intermolecular C‒H···N, C‒H···S and C‒H···π interactions. The energy frameworks for crystal structures of 1–3 were described. The substituent effect on the intermolecular interactions and their contributions were described on the basis of Hirshfeld surface analyses. The 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibition potential, pharmacokinetic and toxicity profiles of compounds 1–3 were determined using in silico techniques. Molecular docking of the compounds into the 11β-HSD1 active site showed comparable binding affinity scores (−7.50 to −8.92 kcal/mol) to the 11β-HSD1 co-crystallized ligand 4YQ (−8.48 kcal/mol, 11β-HSD1 IC50 = 9.9 nM). The compounds interacted with key active site residues, namely Ser170 and Tyr183, via strong hydrogen bond interactions. The predicted pharmacokinetic and toxicity profiles of the compounds were assessed, and were found to exhibit excellent ADMET potential.
Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is mainly prevalent in the older population. Approximately fifty million people are diagnosed with dementia, with AD accounting for 60-70% of these cases. Amyloid beta (Aβ) is considered a pathological hallmark of AD. The shorter Aβ 25 -35 peptide fragments, formed from the amyloidogenic Aβ 1-40 peptide, plays a crucial role in the peptide's neurotoxic activity (Pike et al., 2002). Acetylcholinesterase (AChE) as well as oxidative stress have shown to trigger Aβ formation and aggregation (Belluti et al., 2011; Cheignon et al., 2018). Previously, we synthesized multifunctional edaravone-Nbenzyl pyridinium compounds that exhibited potent AChE inhibition and antioxidant activity as well as predicted to cross the blood-brain barrier (BBB) using in silico models (Zondagh et al., 2020). Method: Selected compounds were chosen to further investigate their AChE inhibitory kinetics, Aβ 25 -35 and MPP + attenuating ability, cytotoxicity and in vitro BBB permeability. The AChE inhibitory kinetics were determined using a modified Ellman's method. The data was analyzed, and a double-reciprocal Lineweaver-Burk plot was drawn. Mode of inhibition was determined from the Lineweaver-Burk plot. The compounds in vitro Aβ 25 -35 and MPP + attenuating activity and cytotoxicity at concentrations of 10 -100 µM was assessed on the SH-SY5Y cell line. The in vitro BBB permeability of the compounds were assessed on the b.End5 cell line. Result: All of the compounds exhibited mixed non-competitive -uncompetitive mode of AChE inhibition which correlate with previous molecular docking studies. Four of the five compounds exhibited no cytotoxic effects to the SH-SY5Y cell line, with some exhibiting proliferating effects. Compound 5a, 5e and 5j caused greater cell proliferation compared to the control at 10 μM. Most of the compounds exhibited significant activity at attenuating MPP + and Aβ 25 -35 . Compounds 5a, 5b and 5e exhibited the most promising attenuating affects over all concentrations. Compound 5e caused greater cell proliferation when compared to the control. Conclusion: These multifunctional compounds exhibited significant neuroprotective effects against neurotoxins, especially against Aβ 25 -35 . The compounds have shown promising activity as potential anti-Alzheimer's agents.
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