Synthesis, density functional theory calculation, molecular docking studies, and evaluation of novel 5-nitrothiophene derivatives for anticancer activity.

Within the scope of this study, new 2-{2-[(5-nitrothiophen-2-yl)methylene]hydrazinyl}thiazole derivatives (2a-j) were synthesized and investigated for their potential anticancer and enzyme inhibition activities. Spectroscopic techniques were used to determine the structures of substances. The anticancer activities of compounds were detected in A549 human lung carcinoma and L929 murine fibroblast cell lines, determining cytotoxicity, apoptosis, mitochondrial membrane integrity, and caspase-3 activation. Compounds 2b bearing 4-nitrophenyl, 2c bearing phenyl, and 2d bearing 4-cyanophenyl moieties were specified with high anticancer activity, acting through an apoptotic pathway with an apoptosis ratio of 9.61%-15.59%. Mitochondrial membrane depolarization was determined to be 25.53% and 22.33% for compounds 2b and 2c, respectively. Furthermore, compound 2c exhibited excellent caspase-3 activation. A molecular docking study was realized with compound 2c on the caspase-3 enzyme. Furthermore, the electronic characteristics of the active compounds were investigated using density functional theory (DFT) at the B3LYP/6-31G (d, p) level. The frontier molecular orbital energy and atomic net charges were examined.

Apoptotic Effect of Novel Benzimidazole Derivatives Bearing Pyridyl/Pyrimidinyl Piperazine Moiety.

BACKGROUND: Benzimidazole derivatives bearing pyridyl/pyrimidinyl piperazine moiety has attracted attention in medicinal chemistry and modern drug discovery since it exhibited a variety of biological activities, including anticancer activity. OBJECTIVE: In this study, we designed and synthesized novel 1-[2-oxo-2-(4-substituted phenyl)ethyl]benzimidazol-2- yl)methyl 4-(2-pyridyl/pyrimidin-2-yl)piperazine-1-carbodithioate derivatives (2a-m). We also investigated their anticancer activities against A549 lung adenocarcinoma and C6 rat glioma cell lines. We further studied the selectivity of the compounds against the NIH/3T3 mouse embryonic fibroblast cell line. Cholinesterase inhibition effects of these compounds were also investigated to measure the relationship between anticancer activity and cholinesterases. METHODS: The cytotoxic activities of these acquired thirteen final compounds were screened using MTT assay on A549, C6, and NIH/3T3 cell lines. Cell proliferation ELISA, BRDU (colorimetric) assay was used to measure the proliferation in replicative cells in which DNA synthesis occurs. Flow cytometric analysis was used to measure apoptotic cell percentages, caspase 3 activity, and mitochondrial membrane depolarised cell percentages. RESULTS: Compounds 2e, 2f, and 2k were shown to be the most active antitumor agents with selective cytotoxicities (the results for A549 were 76.58±6.43, 55.13±5.75, and 32.94±3.02 µM, respectively; and for C6 they were 86.48±3.60, 97.12±30.21, and 59.29±3.95 µM, respectively), high DNA synthesis inhibition rates and high apoptotic cell percentages on both cell lines. CONCLUSION: The results showed that compounds 2e, 2f, and 2k have potential anticancer activity against A549 and C6 cell lines.

Synthesis and Biological Evaluation of New 1,3,4-Oxadiazoles as Potential Anticancer Agents and Enzyme Inhibitors.

BACKGROUND: 1,3,4-Oxadiazoles have been known with a wide variety of pharmacological activities including anticancer activity. OBJECTIVE: In this study, novel 2,5-disubstituted 1,3,4-oxadiazole derivatives were synthesized and evaluated for determining their anticancer, anticholinesterase and lipoxygenase (LOX) inhibitory activity. METHODS: All compounds were tested against C6 rat glioma, A549 human lung carcinoma and NIH/3T3 mouse embryo fibroblast cell lines to define cytotoxic concentrations and apoptosis induction levels which they cause. RESULTS: Many of the compounds exhibited remarkable potency that compounds 2a, 2b, 2e, 2h and 2j against C6 cells and compounds 2a, 2b, 2d, 2g, 2i, 2j against A549 cells were found more active than cisplatin. Compound 2d namely, 2-[(5-(4-aminophenyl)-1,3,4-oxadiazol-2-yl)thio]-1-(4-chlorophenyl)ethan-1-one induced apoptosis of A549 cells with 74.9% whereas cisplatin caused 70.9% percentage. CONCLUSION: Among them, compounds 2d and 2j against A549 cell line, compounds 2b and 2e against both tumor cell lines showed selective cytotoxicity evaluating the inhibition concentration against NIH/3T3 cell line. None of the compounds showed significant acetylcholinesterase (AChE) and lipoxygenase inhibitory activities.

Synthesis and biological evaluation of some pyrazoline derivatives bearing a dithiocarbamate moiety as new cholinesterase inhibitors.

In the present study, new pyrazoline derivatives were synthesized via the reaction of 1-(chloroacetyl)-3-(2-furyl)-5-aryl-2-pyrazolines with sodium salts of N,N-disubstituted dithiocarbamic acids. Each derivative was evaluated for its ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) using a modification of Ellman's spectrophotometric method. The compounds were also investigated for their cytotoxic properties using the MTT assay. The most potent AChE inhibitor was found as compound 7 followed by compounds 27 and 17, when compared with eserine. Compounds effective on AChE carry the 2-dimethylaminoethyl moiety, which resembles the trimethylammonium group and the ethylene bridge of acetylcholine. Among all compounds, compound 7 bearing 2-dimethylaminoethyl and 3,4-methylenedioxyphenyl moieties was also found to be the most effective inhibitor of BuChE. The MTT assay indicated that the effective concentration of compound 7 was lower than its cytotoxic concentration.

Effect of αlipoic acid and silymarin on bladder outlet obstruction.

The aim of the present study was to determine whether the treatment of obstructed rat bladders with αlipoic acid (ALA) and silymarin reverses the biochemical and physiological responses to bladder outlet obstruction (BOO). A total of 32 adult Sprague Dawley rats were divided into four groups (n=8 per group): sham (placebo surgery) animals with no treatment (group 1); control animals with surgically induced BOO (group 2); obstructed rats treated with ALA (group 3); and obstructed rats treated with silymarin (group 4). Histological evaluation, bladder weights, collagen structure, TdT-mediated biotin nick end-labeling (TUNEL), inducible nitric oxide sentase (iNOS) mRNA levels, malondialdehyde (MDA) levels and tumor necrosis factor (TNF) levels were investigated. The ALA-treated group had similar bladder weights, collagen levels and TUNEL positivity and decreased iNOS levels compared with the control group, while the silymarin group exhibited further differences. Serum MDA and TNF-α levels were both decreased in the ALA and silymarin groups. ALA treatment reduced the increased oxidative stress and bladder inflammation caused by BOO and may contribute to the protection of bladder function.

Oxidative stress-mediated myocardiotoxicity of ciprofloxacin and ofloxacin in juvenile rats.

In this study, evaluation of the myocardiotoxic effect potential of ciprofloxacin and ofloxacin in juvenile rats and the role of oxidative stress in heart toxicity was conducted. Doses (25 and 50 mg/kg) of each drug were administered to the rats for 1 week. Serum biochemical cardiotoxicity parameters and tissue malondialdehyde and nitric oxide levels were measured. All measured parameters were found elevated in the drug-treated rats, being the highest in the 50-mg/kg ofloxacin-treated rats. Ciprofloxacin and ofloxacin may cause myocardiotoxicity by inducing the oxidative stress in the heart, and nitric oxide is partly responsible for this toxicity.

The effects of captopril and losartan on erythrocyte membrane Na+/K(+)-ATPase activity in experimental diabetes mellitus.

Diabetes mellitus induces a decrease in sodium potassium-adenosine triphosphatase (Na+/K(+)-ATPase) activity in several tissues in the rat and red blood cells (RBC) and nervous tissue in human patients. This decrease in Na+/K(+)-ATPase activity is thought to play a role in the development of long-term complications of the disease. Angiotensin enzyme inhibitors (ACEi) and angiotensin-II receptor antagonists (ARBs) reduce proteinuria and retard the progression of renal failure in patients with IDDM and diabetic rats. We investigated the effects of captopril and losartan, which are used in the treatment of diabetic nephropathy, on Na+/K(+)-ATPase activity. Captopril had an inhibitory effect on red cell plasma membrane Na+/K+ ATPase activity, but losartan did not. Our study draws attention to the inhibitory effect of captopril on Na+/K+ ATPase activity. Micro and macro vascular complications are preceeding mortality and morbidity causes in diabetes mellitus. There is a strong relationship between the decrease in Na+/K+ ATPase activity and hypertension. The non-sulphydryl containing ACEi and ARBs must be the choice of treatment in hypertensive diabetic patients and diabetic nephropathy.