Ercin Erciyas

Cytotoxic activities of mono and bis Mannich bases derived from acetophenone against Renca and Jurkat cells

Mannich bases of acetophenones have been disclosed to have antitumour and cytotoxic activities. 1-Phenyl-3-dimethylaminopropan-1-one hydrochloride, 1, and related piperidino, 2, and morpholino, 3, derivatives, and compound 4, which is a quaternary form of 1, were synthesized as mono Mannich bases derived from acetophenone. They were converted to corresponding bis Mannich bases, 5-8, to see whether it increases the bioactivity. The biological activity of the compounds was examined by cytotoxicity against mouse renal carcinoma (Renca) and transformed human T-lymphocyte (Jurkat) cell lines. Conversion of mono Mannich bases to corresponding bis Mannich bases remarkably increased the cytotoxicity in most cases. Quaternization procedure also improved the bioactivity in mono derivatives against Jurkat cells. Bis mannich bases 5-7 were found to be more active than 5-fluorouracil (6-23 fold) and melphalan (1.25-5 fold) against Renca cells. Except 2 and 8, the compounds synthesised were found to be more active than 5-fluorouracil (1.2-33 fold) against Jurkat cells.

Interaction of (benzylidene-hydrazono)-1,4-dihydropyridines with β-amyloid, acetylcholine, and butyrylcholine esterases

Approved drugs for the treatment of Alzheimers disease belong to the group of inhibitors of the acetylcholinesterase (AChE) and NMDA receptor inhibitors. However none of the drugs is able to combat or reverse the progression of the disease. Thus, the recently reported promising multitarget-directed molecule approach was applied here. Using the lead compound DUO3, which was found to be a potent inhibitor of the AChE and butyrylcholinesterase (BuChE) as well as an inhibitor of the formation of the amyloid (Abeta) plaque, new non-permanently positively charged derivatives were synthesized and biologically characterized. In contrast to DUO3 the new bisphenyl-substituted pyridinylidene hydrazones 5 are appropriate to cross the blood-brain barrier due to their pK(a) values and lipophilicity, and to inhibit both the AChE and BuChE. More important some of the pyridinylidene hydrazones inhibit the Abeta fibril formation completely and destruct the already formed fibrils significantly.

Mannich bases of phenolic azobenzenes possessing cytotoxic activity

Summary A number of arylazophenols 1 were converted into the corresponding mono Mannich bases 2 from which two quaternary salts 3a,b and an ester 3c were prepared. A series of bis Mannich bases 4 were also synthesized. The angles (θ) made between one of the aryl rings and the adjacent azo linkage were determined by electronic absorption spectroscopy. X-ray crystallographic data were obtained for some of the Mannich bases. The compounds were evaluated against murine P388 D1 and L1210 cells and two human T-lymphocyte (Molt 4, CEM) lines, and most of the derivatives were also screened against a panel of human tumour cell lines. A number of correlations were noted between cytotoxicity and various physicochemical constants as well as some structural features determined by X-ray crystallography. Several of the Mannich bases were shown to have mutagenic properties using the A RK mutatest; the compounds in series 2 and 4 have the ability to penetrate the central nervous system, as revealed by their anticonvulsant properties. While series 2–4 have the potential to deaminate forming ortho quinone methides which would be capable of alkylating cellular thiols, the results of stability studies suggest that the bioactivities noted were due to the molecules per se.

Synthesis and Antimicrobial Activity of Some Pyridinium Salts

Some substituted benzylidenehydrazinylpyridinium derivatives bearing benzyl, ethylphenyl and propylphenyl groups on the pyridinium nitrogen were synthesized and screened for possible antibacterial and antifungal activities against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Candida albicans using the microdilution method. Antimicrobial test results indicated that compounds containing a 3-phenylpropyl chain displayed the highest antimicrobial activity against Staphylococcus aureus and the compound 3d was the most active in the series against all tested bacteria and fungi strains.

1,4-Substituted 4-(1H)-pyridylene-hydrazone-type inhibitors of AChE, BuChE, and amyloid-β aggregation crossing the blood-brain barrier.

Given the fundamentally multifactorial character of Alzheimers disease (AD), addressing more than one target for disease modification or therapy is expected to be highly advantageous. Here, following the cholinergic hypothesis, we aimed to inhibit both acetyl- and butyrylcholinesterase (AChE and BuChE) in order to increase the concentration of acetylcholine in the synaptic cleft. In addition, the formation of the amyloid β fibrils should be inhibited and already preformed fibrils should be destroyed. Based on a recently identified AChE inhibitor with a 1,4-substituted 4-(1H)-pyridylene-hydrazone skeleton, a substance library has been generated and tested for inhibition of AChE, BuChE, and fibril formation. Blood-brain barrier mobility was ensured by a transwell assay. Whereas the p-nitrosubstituted compound 18C shows an anti-AChE activity in the nanomolar range of concentration (IC₅₀=90 nM), the bisnaphthyl substituted compound 20L was found to be the best overall inhibitor of AChE/BuChE and enhances the fibril destruction.

Synthesis and biological activity of pyridinium‐type acetylcholinesterase inhibitors

A novel series of bispyridinium‐type acetylcholinesterase (AChE) inhibitors derived from obidoxime, being active in the lower micromolar range, has been reported recently. According to the hypothesis that shorter pyridinium compounds should exhibit higher activity, a new series of compounds was synthesized that has 2,6‐dichlorobenzyl, 2‐chlorobenzyl and phthalimidomethyl moieties, respectively, at one end of the molecule and that are systematically shortened from the contralateral end. The concentration inhibiting the AChE and butyrylcholinesterase (BChE) by 50% (IC50) was evaluated by means of Ellmans test. Compounds characterized by a phenylpropyl residue at the contralateral end (3) were found to have IC50 values comparable with tacrine. In addition, the affinity of 3c toward the BChE was lower, indicating a lower degree of side effects.

Intramolecular cyclization and cytotoxicities of some Mannich bases of styryl ketones

The extent of intramolecular cyclization in a series of Mannich bases derived from 2-arylidene-1,3-diketones (series 5) was probably influenced by the steric and electronic properties of the different basic groups. Replacement of one of the keto groups in series 5 by hydrogen, methyl, carboethoxy and phenyl functions gave series 6 in which the intramolecular cyclization process was abolished. Evaluation of the compounds versus the EMT6 cells in vitro indicated that cytotoxicity did not appear to be influenced by the ratio of cyclic and acyclic species but in series 6 bioactivity was correlated with the electronic nature of the substituents. Two compounds had approximately one-sixth of the activity of the reference compound, melphalan.Abstract The extent of intramolecular cyclization in a series of Mannich bases derived from 2-arylidene-1,3-diketones (series 5 ) was probably influenced by the steric and electronic properties of the different basic groups. Replacement of one of the keto groups in series 5 by hydrogen, methyl, carboethoxy and phenyl functions gave series 6 in which the intramolecular cyclization process was abolished. Evaluation of the compounds versus the EMT6 cells in vitro indicated that cytotoxicity did not appear to be influenced by the ratio of cyclic and acyclic species but in series 6 bioactivity was correlated with the electronic nature of the substituents. Two compounds had approximately one-sixth of the activity of the reference compound, melphalan.

1H-benzimidazole derivatives as butyrylcholinesterase inhibitors: synthesis and molecular modeling studies

A series of N-{2-[2-(1H-benzimidazole-2-yl)phenoxy]ethyl} substituted amine derivatives were synthesized and tested for their cholinesterase inhibitor activity. Acetylcholinesterase and butyrylcholinesterase inhibitor activities were evaluated in vitro by using Ellman’s method. According to the activity results, all of the compounds displayed moderate acetylcholinesterase inhibitory activity and most of the compounds displayed remarkable butyrylcholinesterase inhibitory activity. Compound 3d was the most active compound in the series and also a selective butyrylcholinesterase inhibitor. Molecular docking studies and molecular dynamic simulations were also carried out.

Original paperIntramolecular cyclization and cytotoxicities of some Mannich bases of styryl ketonesCyclisation intramoléculaire et cytotoxicité de quelques bases de Mannich dérivées de styrylcétones

The extent of intramolecular cyclization in a series of Mannich bases derived from 2-arylidene-1,3-diketones (series 5) was probably influenced by the steric and electronic properties of the different basic groups. Replacement of one of the keto groups in series 5 by hydrogen, methyl, carboethoxy and phenyl functions gave series 6 in which the intramolecular cyclization process was abolished. Evaluation of the compounds versus the EMT6 cells in vitro indicated that cytotoxicity did not appear to be influenced by the ratio of cyclic and acyclic species but in series 6 bioactivity was correlated with the electronic nature of the substituents. Two compounds had approximately one-sixth of the activity of the reference compound, melphalan.Abstract The extent of intramolecular cyclization in a series of Mannich bases derived from 2-arylidene-1,3-diketones (series 5 ) was probably influenced by the steric and electronic properties of the different basic groups. Replacement of one of the keto groups in series 5 by hydrogen, methyl, carboethoxy and phenyl functions gave series 6 in which the intramolecular cyclization process was abolished. Evaluation of the compounds versus the EMT6 cells in vitro indicated that cytotoxicity did not appear to be influenced by the ratio of cyclic and acyclic species but in series 6 bioactivity was correlated with the electronic nature of the substituents. Two compounds had approximately one-sixth of the activity of the reference compound, melphalan.

Synthesis and antileishmanial activity of novel pyridinium-hydrazone derivatives

A series of substituted phenylethylidenehydrazinylpyridinium derivatives bearing methyl, ethyl, propyl, and propylphenyl groups on the pyridinium nitrogen were synthesized and evaluated for in vitro antileishmanial activity against Leishmania tropica by using the microdilution method. Among the tested compounds, 3d, 5c, 3b, and 3c were found to be the most active derivatives against the promastigotes of L. tropica (IC50 values are 6.90, 9.92, 11.69 and 12.03 µM, respectively) and to be more active than reference drug meglumine antimonaite (glucantime) (IC50 value: 20.49 µM). The derivatives investigated in this study may have the potential to be lead compound against leishmanial infection.