New N-(1,3,4-thiadiazole-2-yl)acetamide derivatives as human carbonic anhydrase I and II and acetylcholinesterase inhibitors.

Various carbonic anhydrase (CA) enzyme isoforms are known today. In addition to the use of CA inhibitors as diuretics, antiepileptics and antiglaucoma agents, the inhibition of other specific isoforms of CA was reported to have clinical benefits in cancers. In this study, two groups of 1,3,4-thiadiazole derivatives were designed and synthesized to act as human CA I and II (hCA I and hCA II) inhibitors. The activities of these compounds were tested in vitro and evaluated in silico studies. The activity of the synthesized compounds was also tested against acetylcholinesterase (AChE) to evaluate the relation of the newly designed structures to the activity against AChE. The synthesized compounds were analyzed by 1H NMR,13C NMR and high-resolution mass spectroscopy (HRMS). The results displayed a better activity of all the synthesized compounds against hCA I than that of the commonly used standard drug, Acetazolamide (AAZ). The compounds also showed better activity against hCA II, except for compounds 5b and 6b. Only compounds 6a and 6c showed superior activity against AChE compared to the standard agent, tacrine (THA). In silico studies, including absorption, distribution, metabolism and excretion (ADME) and drug-likeness evaluation, molecular docking, molecular dynamic simulations (MDSs) and density functional theory (DFT) calculations, were compatible with the in vitro results and presented details regarding the structure-activity relationship.Communicated by Ramaswamy H. Sarma.

Novel oxadiazole-thiadiazole derivatives: synthesis, biological evaluation, and in silico studies.

In the search for new anticancer agents, we synthesized a new series of thiazole derivatives carried on thiadiazole-oxadiazole hybrid. Final compounds (5a-5i) were analyzed via 1H NMR, 13C NMR, and HRMS. The pharmacokinetic profile of the targeted compounds was predicted via in silico calculations. Their anticancer properties were determined using MTT method against MCF7 and A549 cell lines. Compounds 5a, 5b and 5c were found more active against MCF7 cells than A549 cells while they were not cytotoxic on L929 healthy cells. Generally, it can be summarized that acetamide moiety has a pivotal role in anticancer activity. For further studies, their aromatase inhibitory activity was evaluated. After determination all these features, the binding modes of the active compounds and the stability and relation of the ligand-enzyme complex were investigated using molecular docking and molecular dynamics simulation studies, respectively. In vitro and in silico studies suggest two important structure-activity relationship (SAR) points that at least one azole ring is essential, and if there is approximately 8.0 ± 0.5 Å distance between the H-bond rich zone of ligand and the heteroaryl ring system of ligand has a major impact on aromatase inhibitory activity. Compounds with small group substitution on thiazole are found potentially may be used for the treatment of anti-breast cancer orally.Communicated by Ramaswamy H. Sarma.

Biological activity evaluation of novel monoamine oxidase inhibitory compounds targeting Parkinson disease.

Aim: Design of 5-methoxy benzofuran hybrids with 2-carbohydrazide and 2-(1,3,4-oxadiazol-2-yl) as potential inhibitors of monoamine oxidase (MAO)-B targeting Parkinson disease. Materials and methods: 12 compounds were synthesized and analyzed via high-resolution mass spectrometry, 1H nuclear magnetic resonance and 13C nuclear magnetic resonance techniques. In vitro fluorometric assay was used to investigate the activity of the synthesized compounds on both MAO-A and MAO-B isozymes. Results: Three compounds - 3a, 3c and 3e - displayed half maximal inhibitory concentration values of 0.051 ± 0.002, 0.038 ± 0.001 and 0.077 ± 0.003 µM in the inhibition of MAO-A and 0.048 ± 0.002, 0.040 ± 0.001 and 0.072 ± 0.002 µM for MAO-B, respectively. A molecular dynamics simulation study showed that compound 3c has poor stability as a complex with MAO-A. Conclusion: Compound 3c may be a potential candidate for the treatment of Parkinson disease.

Design and synthesis of novel enantiopure Bis(5-Isoxazolidine) derivatives: insights into their antioxidant and antimicrobial potential via in silico drug-likeness, pharmacokinetic, medicinal chemistry properties, and molecular docking studies.

A series of novel compounds, mono-5-isoxazolidines, and bis (5-isoxazolidines) derivatives, were prepared as bicycloadducts. The new series of isoxazolidines were designed and synthesized via 1,3-dipolar cycloaddition reaction of nitrones with 3,9-Divinyl-2,4,8,10-tetra oxaspiro (5-5) undecane in the context of new antimicrobial and antioxidant drugs discovery and were fully characterized by FT-IR, 13C-NMR, and 1H-NMR spectroscopy. The physicochemical properties of all the novel cycloadducts, like bioactivity score and lipophilicity, were predicted using calculative methods. Similarly, the pharmacokinetic properties such as metabolism, absorption, distribution, and excretion (ADME) were also predicted. Most of the tested compounds exhibited antimicrobial properties to varying degrees against various bacterial species, including the Gram-negative bacteria Pseudomonas aeruginosa and Escherichia coli, and the Gram-positive bacteria Streptococcus pyogenus and Staphylococcus aureus, Antifungal properties were also observed against the tested fungi like Candida albicans, Aspergillus niger, and Aspergillus clavatus. The activity data exhibited that most compounds have high activity as compared to the standard drugs. In the range of graded doses, the results of some selected compounds revealed that some are high antioxidants while others are moderate or weak antioxidants. As evidenced by the molecular docking studies, the synthesized compounds showed good binding mode better than a standard drug, against the protein of a Pantothenate Synthetase enzyme (PDB-2X3F).

Synthesis of novel thiazolyl hydrazone derivatives as potent dual monoamine oxidase-aromatase inhibitors.

The inhibitory effects of 2-thiazolyl hydrazones on monoamine oxidase enzymes are known for a long time. In this study, a new series of 2-thiazolyl hydrazone derivatives were synthesized starting from 6-methoxy-2-naphthaldehyde. All of the synthesized compounds were investigated in terms of their monoamine oxidase (MAO) inhibitory effects and significant results were found. The results showed that compound 2j potently inhibited MAO-A and MAO-B, while compound 2t strongly and selectively inhibited MAO-B compared to standard drugs. Compounds 2k and 2q exhibited selective and satisfying inhibition on MAO-B. In the aromatase inhibition studies of the compounds, it was determined that compounds 2q and 2u had high inhibitory properties. Molecular docking studies on MAO-A, MAO-B, and aromatase enzymes were carried out for the aforementioned compounds. Additionally, molecular dynamics simulation was studied for compound 2q on MAO-B and aromatase complexes. Finally, the Field-based QSAR study was developed and the structure-activity relationship (SAR) was explained. For the first time, dual inhibitors on MAO and aromatase enzyme were investigated together. The aim of this approach is for finding the potential agents that do not cause the cognitive disorders and may even treat neurodegenerative symptoms, thus, the aim was reached successfully.

Quantification of DNA damage products by gas chromatography tandem mass spectrometry in lung cell lines and prevention effect of thyme antioxidants on oxidative induced DNA damage.

Lung cancer has a high treatment cost and poor prognosis in comparison to other types of cancers. This work was involved in studying oxidative DNA base damage inhibition. Accordingly, standard carvacrol, thymol, thymoquinone with water and water-methanol extract of thyme (Origanum vulgare L. subsp. hirtum (link.) Ietswaart), thyme oil and thyme water were prepared and investigated for their efficacy to inhibit DNA oxidative damage formed by H2O2 in malignant lung cells (A549). The antioxidant capacity by ABTS assay was 271.73 ±â€¯11.45 mg trolox equivalent/mL for thyme oil. HPLC analysis was carried out to determine the contents of different thyme extracts, results showing the presence of carvacrol, thymol, protocatechuic acid, caffeic acid, epicatechin and rosmarinic acid in water and water-methanol extracts while only carvacrol and thymol were found in thyme oil and thyme water. After DNA isolation from the cultured cells, the formed oxidative induced DNA damage products were analysed using GC-MS/MS. It was proven that the antioxidants in the cell culture media have succeeded to inhibit oxidative DNA base damage. Thymoquinone was shown to be the best protectant antioxidant among other antioxidants against the formation of oxidative DNA damage, whereas water-methanol extract of thyme was the best among the plant-sourced samples. Thymoquinone and thyme water-methanol extract were investigated for their efficacy on cultured healthy lung cells (BEAS-2B), and it was proven that they are efficient in protection against the oxidation of DNA of healthy lung cells too.

Investigation of antioxidant ability of grape seeds extract to prevent oxidatively induced DNA damage by gas chromatography-tandem mass spectrometry.

Phenolic compounds have been studied elaborately for their efficacy to improve health and to protect against a wide variety of diseases. Herein this study, different analysis methods were implemented to evaluate the antioxidant properties of catechin and cyanidin using their standard substances and as they found in the grape seeds extracts. Total phenol contents were 107.39±8.94mg GAE/g dw of grape seeds for grape seed extract (GSE) and 218.32±10.66mg GAE/g dw of grape seeds for acid-hydrolyzed grape seed extract (AcGSE). The extracts were analyzed by HPLC-DAD system and the results showed the presence of catechin, gallic acid, chlorogenic acid and ellagic acid in the processed methanolic extract and cyanidin, gallic acid and ellagic acid in the processed acidified methanolic extract. The protective abilities of catechin and cyanidin were tested against the oxidation of DNA. The results showed that cyanidin has better protection of DNA against oxidation than catechin. GSE and AcGSE were revealed to inhibit the oxidatively induced DNA damage. GSE decreased about 57% of damage caused by the Fenton control sample. This study could show new aspects of the antioxidant profiles of cyanidin and catechin.

Ultrasensitive determination of DNA oxidation products by gas chromatography-tandem mass spectrometry and the role of antioxidants in the prevention of oxidative damage.

Oxidative stress is considered as one of the significant causes of DNA damage which in turn contributes to cell death through a series of intermediate processes such as cancer formation, mutation, and aging. Natural sources such as plant and fruit products have provided us with interesting substances of antioxidant activity that could be recruited in protecting the genetic materials of the cells. This study is an effort to discover some of those antioxidants effects in their standard and natural forms by performing an ultrasensitive determination of the products of DNA oxidation using GC-MS/MS. Experiments were used to determine the direct antioxidant activity of the substances contained in the tendrils of Vitis vinifera (var. alphonse) by extracting them and achieving Folin-Ciocalteau and CHROMAC analyses to determine the total phenolic content (TPC) and the antioxidant capacity of the extract, respectively; results revealed a phenolic content of 11.39±0.30mg Gallic Acid Equivalent (GAE)/g of the plant's fresh weight (FW) by Folin-Ciocalteau and 8.17±0.49mg Trolox Equivalent (TE)/g FW by CHROMAC assays. The qualitative analysis of the plant extract by HPLC-DAD technique revealed that two flavonoid glycosides namely rutin and isoquercitrin in addition to chlorogenic acid were contained in the extract. The determination of the DNA oxidation products was performed after putting DNA, rutin and isoquercitrin standard samples with different concentration, and the extract's sample under oxidative stress. Eighteen DNA oxidation products were traced using GC-MS/MS with ultra-sensitivity and the experiments proved a significant decrease in the concentration of the DNA oxidation products when the extract was used as a protectant against the oxidative stress. It is believed by conclusion that the extract of V. vinifera's (var. alphonse) tendrils has a good antioxidant activity; hence it is recommended to be used as a part of the daily healthy food list if possible.