Kadir Ozden Yerdelen

Synthesis and biological evaluation of 1,5-bis(4-hydroxy-3-methoxyphenyl)penta-1,4-dien-3-one and its aminomethyl derivatives

Abstract Aminomethyl derivatives of 1,5-bis(4-hydroxy-3-methoxyphenyl)penta-1,4-dien-3-one, designed as new cytotoxins, were synthesized and evaluated in terms of their cytotoxic activities. The compounds have low CC50 values in the low micromolar range against HL-60 neoplasms and HSC-2, HSC-3 and HSC-4 carcinoma cells. In general, the average CC50 values of these compounds were higher towards HGF, HPC and HPLF non-malignant cells, which reveals the tumour-selectivity of these aminomethyl derivatives, Mannich bases. Using specific concentrations of compounds 4 and 6 caused cleavage of PARP1 in HSC-2 cells but not HGF cells, which may be a contributing factor to cytotoxicities and the tumour-selectivities.

Synthesis of donepezil-based multifunctional agents for the treatment of Alzheimer's disease.

Amyloid beta (Aβ) and cholinesterase enzymes (AChE, BuChE) are important biological targets for the effective treatment of Alzheimers disease. In this study, the aim was to synthesize new donepezil-like secondary amide compounds that display a potent inhibition of cholinesterases and Aβ with antioxidant and metal chelation abilities. All test compounds showed activities against both ChEs and β1-42 inhibition. The most encouraging compound, 20, is an AChE inhibitor with high anti-aggregation activity (55.3%). Based on the results, compound 20 may be a promising structure in further research for new anti-Alzheimers agents.

Design, synthesis and biological activity of 1H-indene-2-carboxamides as multi-targeted anti-Alzheimer agents

Abstract The aim of this study was to design new molecules and evaluate their anticholinesterase and amyloid beta (Aβ1–42) inhibition activities as multifunctional drug candidates for the treatment of Alzheimer’s disease (AD). A series of 5,6-dimethoxy-1H-indene-2-carboxamides (1–22) was synthesized; cholinesterase inhibitory activities of the compounds were measured according to Ellman’s colorimetric assay, while the thioflavin T assay was used for measuring the inhibition of Aβ1–42 aggregation. The results revealed that most compounds showed higher inhibitory activity against BuChE than AChE. Compounds 20 and 21 were found to be the most potent BuChE inhibitors with respective IC50 values of 1.08 and 1.09 μM. Compounds 16, 20, 21 and 22 exhibited remarkable inhibition of Aβ1–42 aggregation. Kinetic analysis showed that the most potent BuChE inhibitor (20) acted as a noncompetitive inhibitor. Docking studies suggested that inhibitor 20 displayed many potential hydrogen-bondings with the PAS of BuChE. These results suggest that compound 20 may be an especially promising multifunctional drug for the prevention and treatment of AD.

Preparation, anticholinesterase activity, and docking study of new 2-butenediamide and oxalamide derivatives

Abstract Several new oxalamide and 2-butenediamide derivatives have been designed, synthesized and evaluated as the acetyl- and butyryl-cholinesterase inhibitors for Alzheimer’s disease. The enzyme inhibitory activity of the synthesized compounds was measured using Ellman’s colorimetric method. It was revealed that compound 1a (N,N′-bis-(4-chloro-benzyl)-N,N′-diphenyl-oxalamide) showed maximum activity against BuChE with a half maximal inhibitory concentration (IC50) = 1.86 µM and compound 2a (but-2-enedioic acid bis-[(4-chloro-benzyl)-phenyl-amide]) exhibited optimum AChE (IC50 = 1.51 µM) inhibition with a high-selectivity index. To better understand the enzyme–inhibitor interaction of the most active compounds towards cholinesterase, molecular modelling studies were carried out. Docking simulations revealed that inhibitors 1a and 2a targeted both the catalytic active site and the peripheral anionic site of 1ACJ and 1P0I.

Microwave-Assisted Synthesis, Molecular Docking, and Cholinesterase Inhibitory Activities of New Ethanediamide and 2-Butenediamide Analogues

A novel series of meta-substituted ethanediamide and 2-butenediamide derivatives were synthesized and tested for their ability to inhibit electric eel acetylcholinesterase (AChE) and equine serum butyrylcholinesterase (BuChE). The synthesized compounds were evaluated against ChE enzymes using the colorimetric method described by Ellman et al. (Biochem. Pharmacol., 7, 1961). It was revealed that some synthesized compounds exhibited high anticholinesterase activity, among which compounds 1f and 2f were the most active inhibitors against BuChE (IC50 value=1.47 µM) and AChE (IC50 value=2.09 µM), respectively. Docking simulations revealed that the inhibitors 1f and 2f are capable of simultaneously binding the peripheral anionic site as well as the catalytic anionic site of both ChE enzymes. These derivatives are considered interesting candidates for Alzheimers disease treatment.

In vitro anticholinesterase activity and molecular docking studies of coumarin derivatives isolated from roots of Heptaptera cilicica

The chloroform extract of the roots of Heptaptera cilicica (Boiss. & Bal.) Tutin (Apiaceae) was investigated in terms of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory effects by Ellman method. Afterwards, a new furocoumarin: trichoclin angelate with five known coumarin derivatives: umbelliprenin, badrakemone, badrakemin, badrakemin acetate and prunate were isolated from this extract. Their structures were identified by means of spectroscopic methods (1D, 2D-NMR and HRESIMS). The next step of our study was determining AChE and BuChE inhibitory activities of the compounds by molecular docking and in vitro methods. According to the results, prunate was found to be the most potent compound, which exhibited significant inhibitory potency against acetylcholinesterase (IC50 = 1.76 ± 0.003 µM) and butyrylcholinesterase (IC50 = 0.21 ± 0.002 μM) as compared with the reference compound, galantamine hydrobromide.

Crystal structure of 1-{4-hy-droxy-3-[(pyrrolidin-1-yl)meth-yl]phen-yl}-3-phenyl-prop-2-en-1-one.

In the title compound, the pyrrolidine ring adopts an envelope conformation, which may be correlated with the intramolecular O—H⋯N hydrogen bond.