Tuba Tüylü Küçükkılınç

Novel multi-targeted agents for Alzheimer's disease: Synthesis, biological evaluation, and molecular modeling of novel 2-[4-(4-substitutedpiperazin-1-yl)phenyl]benzimidazoles

The present study describes the synthesis, pharmacological evaluation (BChE/AChE inhibition, Aβ antiaggregation, and neuroprotective effects), and molecular modeling studies of novel 2-[4-(4-substitutedpiperazin-1-yl)phenyl]benzimidazole derivatives. The alkyl-substituted derivatives exhibited selective inhibition on BChE with varying efficiency. Compounds 3b and 3d were found to be the most potent inhibitors of BChE with IC50 values of 5.18 and 5.22μM, respectively. The kinetic studies revealed that 3b is a partial non-competitive BChE inhibitor. Molecular modeling studies also showed that the alkyl-substituted derivatives were able to reach the catalytic anionic site of the BChE. The compounds with an inhibitory effect on BChE were subsequently screened for their Aβ antiaggregating and neuroprotective activities. Compounds 3a and 3b exerted a potential neuroprotective effect against H2O2 and Aβ-induced cytotoxicity in SH-SY5Y cells. Collectively, 3b was found as the most promising compound for the development of multi-target directed ligands against Alzheimers disease.

Inhibition of electric eel acetylcholinesterase by triarylmethane dyes.

The effects of three cationic triarylmethane dyes--pararosaniline (PR), malachite green (MG), methyl green (MetG)--on electric eel AChE (eAChE) activity were tested at 25 degrees C, in 100 mM MOPS buffer (pH 8) containing 0.125 mM 5-5-dithio-bis(2-nitrobenzoic acid), 20-120 microM acetylthiocholine and 0-20 microM dye. All three dyes caused reversible, linear- or hyperbolic-mixed inhibition of esteratic activity. The respective inhibitory parameters for PR, MG and MetG were K(i)=8.4+/-0.67, 1.9+/-0.51 and 0.27+/-0.017 microM; alpha (competitive coefficient)=5.8+/-2.0, 4.8+/-1.8 and 2.7+/-0.32; beta (noncompetitive coefficient)=0, 0 and 0.20+/-0.011. The data were consistent with ligand binding at the peripheral site and a remote effect on substrate binding and turnover.

Design, Synthesis and In Vitro Study of 5,6-Diaryl-1,2,4-triazine-3-ylthioacetate Derivatives as COX-2 and β-Amyloid Aggregation Inhibitors

In order to find novel cyclooxygenase (COX)‐2 inhibitors for treating inflammatory‐based diseases such as Alzheimers disease (AD), an ethyl carboxylate side chain was added to 5‐(4‐chlorophenyl)‐6‐(4‐(methylsulfonyl)phenyl)‐3‐(methylthio)‐1,2,4‐triazine (lead compound II) to maintain residual inhibition of COX‐1 through interacting with Arg120. A preliminary molecular docking study on both the COX‐1/COX‐2 active sites truly confirmed our hypothesis. Accordingly, a series of ethyl 5,6‐diaryl‐1,2,4‐triazine‐3‐ylthioacetate derivatives were synthesized and their chemical structures were confirmed by NMR, IR and MS spectra. Further in vitro COX‐1/COX‐2 evaluations revealed that compound 6c (COX‐2 IC50 = 10.1 μM, COX‐1 IC50 = 88.8 μM) is the most selective COX‐2 inhibitor while maintaining residual inhibition of COX‐1. In order to evaluate their potential use against AD, an in vitro evaluation of β‐amyloid fibril formation was performed. The results indicated that the prototype compounds 6 are effective β‐amyloid destabilizing agents while compound 6c could inhibit 94% of the β‐amyloid fibril formation after 48 h. Finally, the in silico assessment results of their blood–brain barrier permeability were satisfactory.

1,2-Diaryl-2-hydroxyiminoethanones as Dual COX-1 and β-Amyloid Aggregation Inhibitors: Biological Evaluation and In Silico Study

To find out new agents for treating inflammatory‐involved diseases such as Alzheimers disease, a series of 1,2‐diaryl‐2‐hydroxyiminoethanones containing vicinal diaryl pharmacophore of COX inhibitors were tested by a set of in vitro, in vivo, and computational studies. The in vivo study of compounds indicated their prominent anti‐inflammatory ability at the doses of 10 and 20 mg/kg comparable to celecoxib (10 mg/kg). Further in vitro COX‐1/COX‐2 evaluations revealed that 4‐methoxy derivative 3 had a high selective COX‐1 inhibitory activity (COX‐1, IC50 = 0.12 μm, SI > 833). To evaluate their potential use against Alzheimers disease, in vitro evaluation of β‐amyloid fibril formation using Aβ(1–40) and Aβ(1–42) peptides was performed. The evaluation of their antiaggregation ability gave impressive results and comparable to rifampicin and indomethacin. Conformational study of compound 3 and subsequent docking of its restrained analogs on both active sites of COX‐1 and COX‐2 could provide a proof of its COX‐1 selectivity as well as molecular dynamic simulation could elucidate and give more insight into the amyloid disaggregation mechanisms leading to rational design of inhibitors.

Novel 2-Arylbenzimidazole derivatives as multi-targeting agents to treat Alzheimer’s disease

This study describes the synthesis, pharmacological evaluation, including acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) inhibition, amyloid beta (Aβ) antiaggregation, and neuroprotective effects, as well as molecular modeling of novel 2-(4-substituted phenyl)-1H-benzimidazole derivatives. These derivatives were synthesized by cyclization of o-phenylenediamines with sodium hydroxy(4-substituted phenyl)methanesulfonate salts. In vitro studies indicated that the most of the target compounds showed remarkable inhibitory activity against BChE (IC50: 13.60–95.44 µM). Among them, 3d and 3g-i also exhibited high selectivity (SI ≥ 35.7) for BChE with IC50 values 39.56, 13.60, 14.45, and 15.15 µM, respectively. According to the molecular modeling studies, it may be assumed that the compounds are able to reach the catalytic site of BChE but not that of AChE. The compounds showing BChE inhibitory effects were subsequently examined for their Aβ-antiaggregating and neuroprotective activities. Among the compounds, 3d inhibited the Aβ1–40 aggregation and demonstrated significant neuroprotection against H2O2-induced and Aβ1–40-induced cell death. Collectively, compound 3d showed the best multifunctional activity (BChE; IC50 = 39.56 µM, SI > 126; Aβ self-mediated aggregation; 67.78% at 100 μM; H2O2-induced cytotoxicity with cell viability of 98% and Aβ1-40-induced cytotoxicity with cell viability of 127%). All these results suggested that 2-(4-(4-methylpiperidin-1-yl)phenyl)-1H-benzo[d]imidazole (compound 3d) could be a promising multi-target lead candidate against Alzheimer’s disease.

Synthesis and neuroprotective activity of novel 1,2,4-triazine derivatives with ethyl acetate moiety against H 2 O 2 and Aβ-induced neurotoxicity

A series of 5,6-diaryl-1,2,4-triazine-3-thioacetate derivatives 3a–f, 8a–d and their regioisomer 8e were synthesized. Neuroprotective activity of compounds was assessed against H2O2 and β-amyloid-induced toxicity in PC12 and SH-SY5Y cells respectively. Surprisingly, ethyl 2-(5-(4-chlorophenyl)-6-(4-methoxyphenyl)-3-thioxo-1,2,4-triazin-2(3H)-yl)acetate (8e) was the most potent compound in both tests with EC50 of 14 µM in H2O2 induced apoptosis and also could increase 40% of cell viability revealed by cytometric analysis with Annexin V/PI staining. It was also shown that regioisomer 8e has more neuroprotective activity than Quercetin in β-amyloid induced toxicity. Morphologic evaluation of cells by DAPI staining and TUNEL assay showed the effectiveness of this compound to improve neurite outgrowth in neuronal cells.

Low-dose bisphenol A induces RIPK1-mediated necroptosis in SH-SY5Y cells: Effects on TNF-α and acetylcholinesterase: AYAZGÖK and TÜYLÜ KÜÇÜKKILINÇ

Bisphenol A (BPA) is an endocrine disruptor chemical, which is commonly used in everyday products. Adverse effects of its exposure are reported even at picomolar doses. Effects of picomolar and nanomolar concentrations of BPA on cytotoxicity, nitric oxide (NO) levels, acetylcholinesterase (AChE) gene expression and activity, and tumor necrosis factor‐α (TNF‐α) and caspase‐8 levels were determined in SH‐SY5Y cells. The current study reveals that low‐dose BPA treatment induced cytotoxicity, NO, and caspase‐8 levels in SH‐SY5Y cells. We also evaluated the mechanism underlying BPA‐induced cell death. Ours is the first report that receptor‐interacting serine/threonine‐protein kinase 1–mediated necroptosis is induced by nanomolar BPA treatment in SH‐SY5Y cells. This effect is mediated by altered AChE and decreased TNF‐α levels, which result in an apoptosis‐necroptosis switch. Moreover, our study reveals that BPA is an activator of AChE.

Design, synthesis and evaluation of novel multi-target-directed ligands for treatment of Alzheimer's disease based on coumarin and lipoic acid scaffolds

A novel series of coumarin-lipoic acid conjugates were synthesized via cycloaddition click reaction to find out new multi-target-directed ligands (MTDLs) for treatment of Alzheimers disease (AD). All of synthesized compounds were screened for neuroprotective and anti-cholinesterase activities. Based on primary screening, two compounds (5 and 11) were subjected to further biological evaluations. In particular, compound 11 which was the most potent AChE inhibitor showed good inhibitory effect on Aβ-aggregation and intracellular ROS (reactive oxygen species) formation, as well as the ability of selective bio-metal chelation and neuroprotection against H2O2- and Aβ1-42-induced cytotoxicity. In the light of these results, the applied hybridization approach introduced new promising lead compound with desired multifunctional properties, being useful in the treatment of Alzheimers disease.

Novel 3-phenylcoumarin–lipoic acid conjugates as multi-functional agents for potential treatment of Alzheimer's disease

New series of triazole-containing 3-phenylcoumarin-lipoic acid conjugates were designed as multi-functional agents for treatment of Alzheimers disease. The target compounds 4a-o were synthesized via the azide-alkyne cycloaddition reaction and their biological activities were primarily evaluated in terms of neuroprotection against H2O2-induced cell death in PC12 cells and AChE/BuChE inhibition. The promising compounds 4j and 4i containing four carbons spacer were selected for further biological evaluations. Based on the obtained results, the benzocoumarin derivative 4j with IC50 value of 7.3 µM was the most potent AChE inhibitor and displayed good inhibition toward intracellular reactive oxygen species (ROS). This compound with antioxidant and metal chelating ability showed also protective effect on cell injury induced by Aβ1-42 in SH-SY5Y cells. Although the 8-methoxycoumarin analog 4i was slightly less active than 4j against AChE, but displayed higher protection ability against H2O2-induced cell death in PC12 and could significantly block Aβ-aggregation. The results suggested that the prototype compounds 4i and 4j might be promising multi-functional agents for the further development of the disease-modifying treatments of Alzheimers disease.

Synthesis and cholinesterase inhibitory activity of new 2-benzofuran carboxamide-benzylpyridinum salts

A series of benzofuran-2-carboxamide-N-benzyl pyridinium halide derivatives (6a-o) are synthesized as new cholinesterase inhibitors. The synthetic pathway involves the reaction of salicylaldehyde derivatives and ethyl bromoacetate, followed by hydrolysis and amidation with 3- and 4-picolyl amine. Subsequently, N-((pyridin-4-yl) methyl) benzofuran-2-carboxamide and substituted N-((pyridin-3-yl) methyl) benzofuran-2-carboxamides reacts with benzyl halides to afford target compounds (6a-o). The chemical structures of all derivatives were confirmed by spectroscopic methods. The studies reveal that some of the synthesized compounds are potent butyrylcholinesterase inhibitors with IC50 values in the range of 0.054-2.7 µM. In addition, good inhibitory effects on Aβ self-aggregation are observed for 6h and 6k (33.1 and 46.4% at 100 µM, respectively).