Synthesis, Antioxidant, Cytotoxicity, Induce Apoptosis Investigation and Docking Study of New Halogenated Dihydropyrano[3,2-b]Chromene-3-Carbonitrile Derivatives on MCF-7 Breast Cancer Cell Line.

Background: Chromene derivatives showed numerous biological activities. In the current study, the antioxidant, cytotoxicity, and apoptosis properties of halogenated dihydropyrano[3,2-b]chromene-3-carbonitrile derivatives (HDCCD) on MCF-7 cell line have been examined. Objectives: This study's principal point was synthesizing new halogenated pyranochromene derivatives and assessing their cytotoxic effects and apoptosis potential on MCF-7 breast cancer cell line by flow cytometry. Methods: Initially, 6-chloro- and 6-bromo-3-hydroxychromone compounds were prepared. In the next step, a series of HDCCD were synthesized by a one-pot three-component reaction of these two compounds, aromatic aldehydes, and malononitrile, in the presence of triethylamine in EtOH at reflux conditions. These compounds were fully characterized by standard spectroscopic techniques (IR, 1H, and 13C NMR) and elemental analyses. The potential of the antioxidant activity was determined by using ferric reducing antioxidant power assay (FRAP). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and lactate dehydrogenase (LDH) were used to evaluate metabolic activity. The nitric oxide (NO) and malondialdehyde (MDA) biomarkers of the exposed cells were evaluated on the cells and their supernatant. To quantify apoptotic death of MCF-7 breast cancer cells treated by the compounds at their IC50 concentrations, Annexin V-FITC apoptosis detection kit was utilized. Molecular docking of compounds (6a-j) into the Cyclin-dependent kinase 6 (PDB code: 4EZ5) was carried out, and the probable binding mode of compounds 6e and 6j was determined. Results: A dose-response relationship was seen in all the compounds. Most of them induced cytotoxic effects on the cells. Nitrite concentration of the culture media of the cells was decreased compared to the control. Malondialdehyde levels of the cells were below the range of the control by the addition of 6b, 6d, 6e, 6f, and 6g compounds on the cells, while the addition of the 6a, 6c, 6h, 6i, and 6j compounds increased the MDA level compared to the control. Flow cytometric analysis showed that most of the exposed cells were in the early and late apoptotic stage, and a few of them were in the necrotic stage. Conclusions: It could be concluded that HDCCD (6a-j) was toxic and caused death in the cells by apoptosis. The compounds have lipophilic characteristics, so they can easily pass the cell membrane. As confirmed by LDH results, it can be concluded that the cytotoxicity is connected with apoptosis rather than necrosis, endorsed by flowcytometry analysis afterward.

Synthesis and In Vitro Cytotoxicity of Novel Halogenated Dihydropyrano[3,2-b]Chromene Derivatives.

Lung and breast cancers are among the most common cancers. In the present work, initially, 6-bromo-; and 6-chloro-3-hydroxychromone compounds were prepared. In the next step, a series of 8-bromo-; and 8-chloro-dihyropyrano[3,2-b]chromene derivatives were synthesized by one-pot three component reaction of these two compounds, aromatic aldehydes, and ethyl cyanoacetate in the presence of triethylamine in EtOH at reflux conditions. The synthesized compounds were tested for their in vitro cytotoxic activity against A549 (lung cancer) and MCF-7 (breast cancer) cell lines. It was found that some compounds have high to moderate cytotoxicity, which makes them potential candidates for further studies. This study can be the basis for further studies to design and synthesis potent anticancer compounds and investigating their mechanism of action.

Creating Antibacterial Properties in Flowable Dental Composites by Incorporation of 3, 4-dihydropyrimidin-2(1H)-ones

ABSTRACT Objective: To investigate the antibacterial, mechanical, physical properties and water sorption of flowable dental composites containing 3,4-dihydropyrimidin-2(1H)-ones. Material and Methods: 3,4-dihydropyrimidin-2(1H)-ones was synthesized and the antibacterial activity of flowable dental composites containing 0-5 wt% 3,4-dihydropyrimidin-2(1H)-ones and also of their mechanical and physical properties on flowable dental composites were investigated. Flexural strength was measured by a three-point bending test. Compressive strength (CS), Water sorption (WS) and depth of cure (DOC) were investigated. The data were analyzed by One-way ANOVA test. The level of significance was determined as p<0.01. Results: The direct contact test demonstrates that by increasing the 3,4-dihydropyrimidin-2(1H)-ones content, the bacterial growth is significantly diminished (p<0.001). The average flexural strength results show that with increasing 3,4-dihydropyrimidin-2(1H)-ones until 3% in the composite, no significant difference was observed in flexural strength (p>0.001) and the mean of compressive strength results show no significant difference between 0-4% groups (p>0.001). The mean of water sorption and depth of cure results shows no significant difference between groups (p>0.001). Conclusion: Incorporation of 3,4-dihydropyrimidin-2(1H)-ones into flowable resin composites in 3% wt can reduce the activity of Streptococcus mutans.

Biocompatibility of a New Antibacterial Compound and its Effect on the Mechanical Properties of Flowable Dental Composites (Animal Study).

STATEMENT OF THE PROBLEM: Recently, new compound of 3, 5-dimethyl-1-thiocarboxamide pyrazole has been composed with excellent antibacterial property. Biocompatibility and its effects on mechanical properties of dental composites should be considered before clinical use. PURPOSE: The purpose of this study was to evaluate the biocompatibility of 3, 5-dimethyl-1-thiocarboxamide pyrazole as a new antibacterial compound and its effect on the mechanical properties of dental composites. MATERIALS AND METHOD: In this experimental study, a new antibacterial compound was synthesis by reaction between Thiosemicarbazide and 2, 4-Pentandione and tested on thirty male albino Wistar rats weighting 200-250gr. Rats were randomly divided into 3 groups of 10, each rat received 3 implants of 3,5-dimethyl-1-thiocarboxamide pyrazole, penicillin v and empty polyethylene tube. A pathologist, who was unaware of types of tested materials and timing, performed the examination of specimens. The depth of cure and flexural strength of resin composite was measured using Iso4049 standard technique. Compressive strength was determined according to Iso9917 standard. RESULTS: This compound was biocompatible and there was no significant difference in flexural strength and compressive strength of the composites containing 1% of this compound with the control group (p> 0.05). CONCLUSION: The 3, 5-dimethyl-1-thiocarboxamide pyrazole with a concentration of 1% in flowable composites can be very effective in preventing secondary caries.

Metronidazole aryloxy, carboxy and azole derivatives: Synthesis, anti-tumor activity, QSAR, molecular docking and dynamics studies.

A series of novel metronidazole aryloxy, carboxy and azole derivatives has been synthesized and their cytotoxic activities on three cancer cell lines were evaluated by MTT assay. Compounds 4m, 4l and 4d showed the most potent cytotoxic activity (IC50s less than 100 µg/mL). Apoptosis was also detected for these compounds by flow cytometry. Docking studies were performed in order to propose the probable target protein. In the next step, molecular dynamics simulation was carried out on the proposed target protein, focal adhesion kinase (FAK, PDB code: 2ETM), bound to compound 4m. As, 4m showed a potent cytotoxic activity and an acceptable apoptotic effect, it can be a potential anticancer candidate that may work through inhibition of FAK.

Design, Synthesis, Biological Evaluation and Molecular Modeling Study of Novel Indolizine-1-Carbonitrile Derivatives as Potential Anti-Microbial Agents.

A novel one-pot two step tandem reaction for the synthesis of indolizine-1-carbonitrile derivatives (5a-i) was identified. The route comprises 1,3-dipolar cycloaddition reaction of aromatic aldehyde derivatives (1a-i), malononitrile (2) and 1-(2-(4-bromophenyl)-2-oxoethyl)-2-chloropyridin-1-ium (4) under ultrasound irradiation at room temperature in the presence of triethylamine at acetonitrile. The product compounds were tested against bacteria and fungi. It was revealed that compound 5b had the most antifungal activity (range MICs = 8-32 µg/mL) and compound 5g had the most antibacterial activity (range MICs = 16-256 µg/mL). Molecular docking of compounds (5a-i) into fungal 14α-demethylase and bacterial protein tyrosine phosphatase active sites were also performed and probable binding mode of compounds 5b and 5g were determined.

Ultrasound-assisted 1,3-dipolar cycloaddition and cyclopropanation reactions for the synthesis of bis-indolizine and bis-cyclopropane derivatives.

Ultrasound irradiation can promote the 1,3-dipolar cycloaddition reaction of 2-chloropyridinium ylides with 2-benzylidenemalononitrile or 2,2'-(1,4-phenylenebis(methanylylidene))dimalononitrile, to afford the indolizine and bis-indolizine derivatives respectively. While the reaction of pyridinium ylides with 2-benzylidenemalononitrile or 2,2'-(1,4-phenylenebis(methanylylidene))dimalononitrile under ultrasound irradiation provided, in an unusual manner, cyclopropane and bis-cyclopropane derivatives, respectively. These cycloaddition and cyclopropanation reactions were carried out in the presence of triethylamine, in acetonitrile, at room temperature.