(E)-1-(4-Hydroxyphenyl)-3-(substituted-phenyl)prop-2-en-1-ones: Synthesis, In Vitro Cytotoxic Activity and Molecular Docking Studies.

A series of chalcone compounds (2-11) were designed and synthesized to determine their cytotoxic effects. The structures of 2-11 were fully characterized by their physical and spectral data. The in vitro cytotoxic effects of 2-11 were evaluated against human ovarian cancer (A2780), breast cancer (MCF-7) and prostate cancer (PC-3 and LNCaP) cell lines. The activity potentials of compounds were further evaluated through molecular docking studies with AutoDock4 and Vina softwares. All the compounds (except compound 5) showed significant cytotoxic effects at high doses in all cancer cell lines. Among all the compounds studied, one compound i.e. compound 2 demonstrated dose-dependent activity, particularly against A2780/LNCaP cancer cell lines. The most effective compounds 8, 9, 10 and 11 reduced the cell viability of A2780, MCF-7, PC-3 and LNCaP cells by 50-98%, while other compounds 2, 4 and 7 reduced the cell viability of A2780 cells by 70-90% at concentrations of 50 and 100 µM.

In vitro effects of thirty-eight cardiac drugs on human serum paraoxonase.

In this study, the effects of 38 commonly used cardiac drugs on the human paraoxonase (PON1) were investigated. PON1 was purified from human serum blood by ammonium sulfate precipitation (60%-80%) and hydrophobic interaction chromatography (Sepharose-4B~L-tyrosine~1-napthylamine gel). All of the cardiac drugs inhibited PON1 at the micro molar level. IC50 and Ki values were determined for each drug. The tested drugs displayed potent PON1 inhibitory activity. It was found that the weakest PON1 inhibitors are Irbesartan (Ki : 421.73 µM), Glyceryl Trinitrate (Ki : 351.48 µM), and Apixaban (Ki : 333.27 µM). Bisoprolol hemifumarate (Ki : 269.31 µM) is also other weak PON1 inhibitor. Therefore, these drugs, having weak PON1 inhibitory activity, may be preferred primarily in patients with atheroclerotic heart disease compared to other drugs due to the protective effect of PON1 on atherosclerosis. Conversely, the most potent inhibitors against PON1 were propafenone (Ki : 0.35 µM), Lacidipine (Ki : 0.78 µM), Lidocaine HCl (Ki : 1.78 µM), and Propranolol (Ki : 1.86 µM). Molecular docking was also applied to confirm the activity of some cardiac drugs on PON1.

Ellagic acid inhibits proinflammatory intermediary manufacture by suppressing NF-κB/Akt, VEGF and activating Nrf-2/Caspase-3 signaling pathways in rat testicular damage: a new way for testicular damage cure and in silico approach.

Ellagic acid (EA) has protective effect on testicular damage and this natural compound decreases oxidative damage. The present study aims to examine the preventive effect of ellagic acid (EA) against carbon tetrachloride (CCl4)-induced testicular tissue damage in rats. In testicular tissue, tumor necrosis factor-α (TNF-α), Nuclear factor erythroid-2 related factor 2 (Nrf-2), B-cell lymphoma-2 (Bcl-2), vascular endothelial growth factor (VEGF), Nuclear factor-kappa B (NF-κB), cysteine aspartic proteases (caspase-3) and protein kinase B (Akt) synthesis levels were analyzed by western blot method, reactive oxygen species (ROS) was measured by malondialdehyde (MDA) levels, Glutathione (GSH) level and catalase (CAT) by spectrophotometer. As a result, in comparison with the CCl4 group, caspase-3 and Nrf-2 protein synthesis levels increased in EA + CCl4 group, however, VEGF, Bcl-2, NF-κB, TNF-α and Akt protein synthesis levels decreased, EA application raised GSH levels and CAT activity, reduced MDA levels. In this study, in silico tools were applied to confirm the activity of EA against the cancer with macromolecules such as the above mentioned transcription factors. EA, turned out to show significant activity similarly to some cocrystal ligands, particularly against cancer. These results points out that EA can be used as a testicular damage cure drug in future.

In vivo, in vitro and in silico anticancer investigation of fullerene C60 on DMBA induced breast cancer in rats.

AIMS: The aim of the study was to determine the protective and therapeutic effect of fullerene C60 nanoparticle on DMBA-induced breast cancer in rats. MAIN METHODS: In vitro cell viability was determined by the WST-1 test. In vivo analysis was performed in female Wistar Albino rats. The expression of caspase-3, Bcl-2, Nrf-2, NF-κB, TNF-α, COX-2, p53, IL-6, IL-1α ve p38α (MAPK) proteins were assessed by western blotting. Furthermore, malondialdehyde (MDA), glutathione (GSH), catalase activity (CAT), total protein levels and DNA damage were investigated. In addition, tissues were evaluated by histopathologically. In in silico analysis, the binding affinities of the fullerene C60 nanoparticle to transcription factors such as caspase-3, Bcl-2, Nrf-2, NF-κB, TNF-α, COX-2, VEGF and Akt were demonstrated by molecular docking. KEY FINDINGS: Treatment of MCF-7 cells at various concentrations of fullerene C60 (0.1 to 100 mg/ml) inhibited cell viability in a dose dependent manner. Fullerene C60 treated rats exhibited considerable increase in the level of caspase-3 while decrease in the level of pro-survival protein Bcl-2. Bcl-2, NF-κB, TNF-α, COX-2, IL-6, IL-1α and p38α (MAPK) protein expression levels and malondialdehyde (MDA) levels were decreased in the C60 + DMBA groups compared to the DMBA group. It was observed that caspase-3, Nrf-2 and p53 protein expression levels, glutathione (GSH) level, catalase activities (CAT) and total protein levels increased significantly which was further confirmed through the resulting DNA fragmentation. SIGNIFICANCE: In silico assays, fullerene C60 has been observed to have similar affinity to some crystal ligands, especially against cancer.

Histological assessment of liver and stomach damage caused by pyridazinone derivative antidepressant agents.

Depression is a serious psychological disorder that affects a significant population. We investigated the antidepressant activities of four pyridazinone derivatives that contain the hydrazide moiety using the forced swimming test (FST). The compounds tested exhibited good antidepressant activity compared to duloxetine. The most promising compound was compound 2, which reduced the duration of immobility during FST. The toxic effects of the four compounds on the histomorphology of the liver and stomach tissue also was evaluated.

Synthesis and spectroscopic characterizations of hexakis[(1-(4'-oxyphenyl)-3-(substituted-phenyl)prop-2-en-1-one)]cyclotriphosphazenes: their in vitro cytotoxic activity, theoretical analysis and molecular docking studies.

The hexachlorocyclotriphosphaze compound (N3P3Cl6, HCCP) was reacted with excess (E)-(1-(4'-oxyphenyl)-3-(substituted-phenyl)prop-2-en-1-ones (2-11) to produce hexakis[(1-(4-oxyphenyl)-3-(substituted-phenyl)prop-2-en-1-one)]cyclotriphosphazenes (CP 2-11). The structures of products (CP 2-11) were confirmed using elemental analysis, FT-IR, MS spectral analysis as well as 31P, 1H and 13C-APT NMR techniques and their thermal properties determined by TGA and DSC techniques. The HOMO-LUMO energy gap and chemical reactivity identifiers were calculated and HOMO and LUMO images were viewed. According to the calculations, all the chemical potential values of CP 2-11 are negative and it shown that the molecules are stable. The in vitro cytotoxic of CP 2-11 investigated and their activity potentials were evaluated by molecular docking studies with Autodock Vina softwares. CP 2-11 compounds were found to demonstrate cytotoxic activity against human cancer cell lines (A2780, LNCaP and PC-3). The CP 2-11 compounds reduced the cell viability against all cancer cell lines in the range 36%-90% especially. The results showed that these compounds are powerful candidate molecules for pharmaceutical applications.

Design, synthesis, in vitro, and in silico studies of 1,2,4-triazole-piperazine hybrid derivatives as potential MAO inhibitors.

Monoamine oxidases (MAOs) have become promising drug targets for the development of central nervous system agents. In recent research, it was shown that numerous piperazine derivatives exhibit hMAO inhibitory activity. Therefore, in this study, a novel series of 1,2,4-triazole-piperazine derivatives (5a-j) were designed, synthesized, characterized, and screened for their hMAO-A and hMAO-B inhibitory activities. When the ADME predictions were examined, it was seen that the pharmacokinetic profiles of all synthesized compounds were appropriate. Compounds 5a, 5b, 5c, and 5e, with H, F, Cl, and NO2 groups on the 4-position of the phenyl ring, respectively, showed important MAO-A inhibitory activity. Compound 5c was found to be the most effective agent among the synthesized compounds with an IC50 value of 0.070 ± 0.002 µM against the MAO-A enzyme. The synthesized compounds appear to support the results of other studies to design MAO inhibitors to obtain more suitable drugs, especially for neurological disorders such as depression and anxiety.

Synthesis, molecular modelling and biological activity of some pyridazinone derivatives as selective human monoamine oxidase-B inhibitors.

BACKGROUND: Since brain neurotransmitter levels are associated with the pathology of various neurodegenerative diseases like Parkinson and Alzheimer, monoamineoxidase (MAO) plays a critical role in balancing these neurotransmitters in the brain. MAO isoforms appear as promising drug targets for the development of central nervous system agents. Pyridazinones have a broad array of biological activities. Here, six pyridazinone derivatives were synthesized and their human monoamine oxidase inhibitory activities were evaluated by molecular docking studies, in silico ADME prediction and in vitro biological screening tests. METHODS: The compounds were synthesized by the reaction of different piperazine derivatives with 3 (2H)-pyridazinone ring and MAO-inhibitory effects were investigated. Docking studies were conducted with Maestro11.8 software. RESULTS: Most of the synthesized compounds inhibited hMAO-B selectively except compound 4f. Compounds 4a-4e inhibited hMAO-B selectively and reversibly in a competitive mode. Compound 4b was found as the most potent (ki = 0.022 ± 0.001 µM) and selective (SI (Ki hMAO-A/hMAO-B) = 206.82) hMAO-B inhibitor in this series. The results of docking studies were found to be consistent with the results of the in vivo activity studies. Compounds 4a-4e were found to be non-toxic to HepG2 cells at 25 µM concentration. In silico calculations of ADME properties indicated that the compounds have good pharmacokinetic profiles. CONCLUSION: It was concluded that 4b is possibly recommended as a promising nominee for the design and development of new pyridazinones which can be used in the treatment of neurological diseases.

A Series of New Hydrazone Derivatives: Synthesis, Molecular Docking and Anticholinesterase Activity Studies.

BACKGROUND: Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are known to be serine hydrolase enzymes responsible for the hydrolysis of acetylcholine (ACh), which is a significant neurotransmitter for regulation of cognition in animals. Inhibition of cholinesterases is an effective method to curb Alzheimer's disease, a progressive and fatal neurological disorder. OBJECTIVE: In this study, 30 new hydrazone derivatives were synthesized. Then we evaluated their anticholinesterase activity of compounds. We also tried to get insights into binding interactions of the synthesized compounds in the active site of both enzymes by using molecular docking approach. METHODS: The compounds were synthesized by the reaction of various substituted/nonsubstituted benzaldehydes with 6-(substitute/nonsubstituephenyl)-3(2H)-pyridazinone-2-yl propiyohydrazide. Anticholinesterase activity of the compounds was determined using Ellman's method. Molecular docking studies were done by using the ADT package version 1.5.6rc3 and showed by Maestro. RMSD values were obtained using Lamarckian Genetic Algorithm and scoring function of AutoDock 4.2 release 4.2.5.1 software. RESULTS: The activities of the compounds were compared with galantamine as cholinesterase enzyme inhibitor, where some of the compounds showed higher BChE inhibitory activity than galantamine. Compound F111 was shown to be the best BChE inhibitor effective in 50 µM dose, providing 89.43% inhibition of BChE (IC50=4.27±0.36 µM). CONCLUSION: This study supports that novel hydrazone derivates may be used for the development of new BChE inhibitory agents.

Conventional and microwave prompted synthesis, antioxidant, anticholinesterase activity screening and molecular docking studies of new quinolone-triazole hybrids.

The synthesis of ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylates (4, 5) was performed via the reaction of corresponding anilines with diethyl ethoxymethylenemalonate under conventional and also microwave promoted conditions. The treatment of 4 and 5 afforded the corresponding hydrazides (6 and 7). These hydrazides were converted to the corresponding carbo(thio)amides (9a-f and 10a-e) which were then subjected to an intramolecular cyclisation leading to the formation of quinolone-triazole hybrids (11a-f and 12a-e). The newly synthesized compounds were screened for their biological activities such as antioxidant capacity (AC) and acetylcholinesterase Activity. Inhibition of cholinesterases is an effective method to curb Alzheimer's disease, a progressive and fatal neurological disorder. A series of some novel quinolonederivatives were designed, synthesized, and their inhibitory effects on AChE were evaluated. We obtained our compounds and determined their anticholinesterase activities according to the Ellman's method. 9b and 10c showed the best AChE inhibition with 0.48 ±â€¯0.02 and 0.52 ±â€¯0.07, respectively. Docking studies were performed for the most active compounds (9b, 10c) and interaction modes with enzyme active sites were determined. As a result of these studies, a strong interaction between these compounds and the active sites of AChE enzyme was revealed.

New (arylalkyl)azole derivatives showing anticonvulsant effects could have VGSC and/or GABAAR affinity according to molecular modeling studies.

(Arylalkyl)azoles (AAAs) emerged as a novel class of antiepileptic agents with the invention of nafimidone and denzimol. Several AAA derivatives with potent anticonvulsant activities have been reported so far, however neurotoxicity was usually an issue. We prepared a set of ester derivatives of 1-(2-naphthyl)-2-(1H-1,2,4-triazol-1-yl)ethanone oxime and evaluated their anticonvulsant and neurotoxic effects in mice. Most of our compounds were protective against maximal electroshock (MES)- and/or subcutaneous metrazol (s.c. MET)-induced seizures whereas none of them showed neurotoxicity. Nafimidone and denzimol have an activity profile similar to that of phenytoin or carbamazepine, both of which are known to inhibit voltage-gated sodium channels (VGSCs) as well as to enhance γ-aminobutiric acid (GABA)-mediated response. In order to get insights into the effects of our compounds on VGSCs and A-type GABA receptors (GABAARs) we performed docking studies using homology model of Na+ channel inner pore and GABAAR as docking scaffolds. We found that our compounds bind VGSCs in similar ways as phenytoin, carbamazepine, and lamotrigine. They showed strong affinity to benzodiazepine (BZD) binding site and their binding interactions were mainly complied with the experimental data and the reported BZD binding model.

Functionalized imidazolium and benzimidazolium salts as paraoxonase 1 inhibitors: Synthesis, characterization and molecular docking studies.

Paraoxonase (PON) is a key enzyme in metabolism of living organisms and decreased activity of PON1 was acknowledged as a risk for atherosclerosis and organophosphate toxicity. The present study describes the synthesis, characterization, PON1 inhibitory properties and molecular docking studies of functionalized imidazolium and benzimidazolium salts (1a-5g). The structures of all compounds were elucidated by IR, NMR, elemental analysis and structures of compounds 2b and 2c were characterized by single-crystal X-ray diffraction. Compound 1c, a coumarin substituted imidazolium salt showed the best inhibitory effect on the activity of PON1 with good IC50 value (6.37 µM). Kinetic investigation was evaluated for this compound and results showed that this compound is competitive inhibitor of PON1 with Ki value of 2.39 µM. Molecular docking studies were also performed for most active compound 1c and one of least active compound 2c in order to determine the probable binding model into active site of PON1 and validation of the experimental results.

Some coumarins and benzoxazinones as potent paraoxonase 1 inhibitors.

In this study, we aimed to investigate the effect of some coumarin and benzoxazinone derivatives on the activity of human PON1. Human serum paraoxonase 1 was purified from fresh human serum blood by two-step procedures that are ammonium sulfate precipitation (60-80%) and then hydrophobic interaction chromatography (Sepharose 4B, L-tyrosine and 1-napthylamine). The enzyme was purified 232-fold with a final specific activity of 27.1 U/mg. In vitro effects of some previously synthesized ionic coumarin or benzoxazinone derivatives (1-21) on purified PON1 activity were investigated. Compound 14 (1-(2,3,4,5,6)-pentamethylbenzyl-3-(6,8-dimethyl-2H-chromen-2-one-4-yl))benzimidazolium chloride was found out as the strongest inhibitor (IC50 = 7.84 µM) for PON1 among the compounds. Kinetic investigation and molecular docking study were evaluated for one of the most active compounds (compound 12) and obtained data showed that this compound is competitive inhibitor of PON1 and interact with Leu262 and Ser263 in the active site of PON1. Moreover, coumarin derivatives were found out as the more potent inhibitors for PON1 than benzoxazinone derivatives.

Coumarin or benzoxazinone based novel carbonic anhydrase inhibitors: synthesis, molecular docking and anticonvulsant studies.

Among many others, coumarin derivatives are known to show human carbonic anhydrase (hCA) inhibitory activity. Since hCA inhibition is one of the underlying mechanisms that account for the activities of some antiepileptic drugs (AEDs), hCA inhibitors are expected to have anti-seizure properties. There are also several studies reporting compounds with an imidazole and/or benzimidazole moiety which exert these pharmacological properties. In this study, we prepared fifteen novel coumarin-bearing imidazolium and benzimidazolium chloride, nine novel benzoxazinone-bearing imidazolium and benzimidazolium chloride derivatives and evaluated their hCA inhibitory activities and along with fourteen previously synthesized derivatives we scanned their anticonvulsant effects. As all compounds inhibited purified hCA isoforms I and II, some of them also proved protective against Maximal electroshock seizure (MES) and ScMet induced seizures in mice. Molecular docking studies with selected coumarin derivatives have revealed that these compounds bind to the active pocket of the enzyme in a similar fashion to that previously described for coumarin derivatives.