Synthesis, Molecular Docking, biological potentials, and Structure-Activity Relationship of new quinazoline & quinazoline-4-one derivatives

Context: Quinazolines are a common class of nitrogen-containing heterocyclic scaffolds exhibiting a broad spectrum of pharmacological activities. Objective: In the present study, quinazoline and quinazolin-4-one derivatives were prepared, characterized to evaluate their biological which may pave the way for possible therapeutic applications. Materials amp; Methods: A new derivative of quinazoline and quinazolin-4-one derivatives was prepared and tested for antiulcerogenic, anti-inflammatory and hepatoprotective activity. Results: The synthesized compounds were characterized by elemental analysis and spectral data. Also, the median lethal doses (LD50s) of compounds 1-3 in rats were 1125, 835 and 1785 mg/kg b.w., respectively. IC50 values of compounds (1-3) as measured by ABTS+ radical method was 0.8, 0.92 and 0.08 mg/mL, respectively. Antiulcerogenic activities at dose 1/20 LD50 in albino rats were 47.94, 24.60 and 56.45%, respectively. Anti-inflammatory effect at dose 1/20 LD50 of compounds (1-3) induced edema model after 120 min. The prepared compounds possess hepato gastric mucosa protective activity against ibuprofen-induced ulceration and LPS-induced liver toxicity, respectively in rats via normalization of oxidative stress biomarkers and inflammatory mediators were inhibited in peritoneal macrophage cells at concentration of 100 µg/L. Molecular docking suggested that the most active compounds 1 and 2 can be positioned within the active sites of COX-2 at Arg121 & Tyr356 similar to ibuprofen (Arg-120, Glu-524, and Tyr-355). The compound 3–COX-2 complex generated by docking revealed intricate interactions with a COX-2 channel. Conclusion: These findings suggest that compounds 1-3 exhibited good antioxidant, antiulcer, anti-inflammatory activity and safe on liver enzymes in rats.

Essential Oil from Melaleuca leucadendra: Antimicrobial, Antikinetoplastid, Antiproliferative and Cytotoxic Assessment

Essential oils (EOs) are known for their use in cosmetics, food industries, and traditional medicine. This study presents the chemical composition and therapeutic properties against kinetoplastid and eukaryotic cells of the EO from Melaleucaleucadendra (L.) L. (Myrtaceae). Forty-five compounds were identified in the oil by GC-MS, containing a major component the 1,8-cineole (61%). The EO inhibits the growth of Leishmania amazonensis and Trypanosoma brucei at IC50 values <10 μg/mL. However, 1,8 cineole was not the main compound responsible for the activity. Against malignant (22Rv1, MCF-7, EFO-21, including resistant sublines MCF-7/Rap and MCF-7/4OHTAMO) and non-malignant (MCF-10A, J774A.1 and peritoneal macrophage) cells, IC50 values from 55 to 98 μg/mL and from 94 to 144 μg/mL were obtained, respectively. However, no activity was observed on Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, Aspergillus niger, Candida parapsilosis, Microsporum canis, or Trypanosoma cruzi. The EO was able to control the lesion size and parasite burden in the model of cutaneous leishmaniasis in BALB/c mice caused by L. amazonensis compared to untreated animals (p < 0.05) and similar with those treated with Glucantime® (p > 0.05). This work constitutes the first evidence of antiproliferative potentialities of EO from M. leucadendra growing in Cuba and could promote further preclinical investigations to confirm the medical value of this plant, in particular for leishmaniasis treatment.

Anti-Inflammatory Effects of Canavalia gladiata in Macrophage Cells and DSS-Induced Colitis Mouse Model

Canavalia gladiata, known as sword bean, has been used as a Chinese traditional medicine for anti-inflammatory effects. However, the action mechanisms of sword bean have not yet been clearly defined. In the present study, the whole parts of a ripened sword bean (RSB) and the green sword bean (GSB) containing bean pod were extracted with ethanol by reflux extraction. The two crude extracts (RSBE and GSBE) from RSB and GSB were validated by a liquid chromatography-tandem mass spectrometry (LC/MS/MS) analysis of gallic acid as a reference chemical. The anti-inflammatory effects of two sword bean extracts were extensively investigated using LPS-stimulated macrophage cells. First, RSBE and GSBE significantly inhibited the production of pro-inflammatory mediators, such as tumor necrosis factor-[Formula: see text] (TNF-[Formula: see text]), interleukin-6 (IL-6), prostaglandinE2 (PGE2), and nitric oxide (NO) in LPS-induced RAW264.7 cells. RSBE and GSBE showed no cytotoxicity to RAW264.7 cells and mouse peritoneal macrophage cells. In addition, the overexpression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) induced by LPS in RAW264.7 cells was significantly decreased by RSBE and GSBE. Western blotting and immunostaining analysis showed that RSBE and GSBE inhibited the nuclear translocation of NF-[Formula: see text]B subunits, which correlated with the inhibitory effects on inhibitor kappa B (I[Formula: see text]B) degradation. In dextran sulfated sodium (DSS)-induced colitis mice model, RSBE restored body weight, colon length, and the levels of pro-inflammatory cytokines, such as TNF-[Formula: see text], IL-6, interleukin-1[Formula: see text] (IL-1[Formula: see text]), and interferon-[Formula: see text] (IFN-[Formula: see text]). In addition, RSBE significantly suppressed the expression of COX-2, iNOS, and NF-[Formula: see text]B.

Effects of Various Carbon Nanotube Suspensions on A549, THP-1, and Peritoneal Macrophage Cells

The effects of iron content, fiber length, and stability of carbon nanotube (CNT) suspension on cells were examined. Five kinds of single-wall carbon nanotube (SWCNT) suspensions were prepared: with catalytic iron, without iron, long SWCNTs (stable), short SWCNTs (stable), and short SWCNT (unstable). These suspensions were applied to A549, THP-1, and mouse peritoneal macrophage cells. After a 24-h exposure, the mitochondrial activity, cell membrane damage, intracellular oxidative stress, and expression of cytokine genes were determined. Among these properties of SWCNTs, stability of CNT suspension had the most influence on the cells, whereas the effects of iron content and fiber length were small. The unstable SWCNT suspension caused a substantial increase in intracellular ROS levels. Additionally, the cellular effects of stable multi-wall carbon nanotubes (MWCNTs) were examined. The MWCNT suspension did not show any cellular effects. Overall, influences of CNT suspension on mitochondrial activity and cell membrane damage were small. These results suggest that the physical properties of CNT suspension are important factors for their cellular effects. Thus, CNT suspensions prepared with the same material but having different physical properties would differ in the cellular effects they exert, including cytotoxicity. Therefore, physical characterization of CNT suspensions is essential to the evaluation of CNT toxicity. In particular, stability of CNT suspension notably influenced the intracellular ROS level.

Effect of Polysaccharides from Fresh Persimmon (Diospyros kaki) Fruits and its Sulfated Derivates on the Immunomodulatory Activity of Mouse Peritoneal Macrophage Cells

The effects of polysaccharides extracted from persimmon (Diospyros kaki) fruits (PFP) and its sulfated derivates (PFP-S) on activity of mouse peritoneal macrophages (PM) were evaluated by measuring their effects on the viability, nitric oxide (NO) production, cytokine (TNF-α, IL-10 and IL-2) production and gene expression. The results showed that both PFP and PFP-S significantly increased the viability and the productions of NO, TNF-α and IL-10 with the increase of the substitution degree (DS) and dose. Of the fractions, PFP-SIII (DS 2.5, Mw 48kDa) was the most potent inducer of NO and cytokine production, increasing production of NO and expression of cytokines (IL-10 and TNF-α). It was supposed from this result that PFP-S might act as an inducer of macrophage functions against pathogens, which might be affected by the sulfate content of polysaccharides made great role in regulate of immunomodulatory activities.

Lichen Metabolites Modulate Hydrogen Peroxide and Nitric Oxide in Mouse Macrophages

The activities of perlatolic acid (1), atranorin (2), and lecanoric acid (3) and their derivatives, such as orsellinates and β-methyl orsellinates obtained by alcoholysis, were assessed for stimulation of the release of hydrogen peroxide and nitric oxide in cultures of peritoneal macrophage cells from mice. The hydrogen peroxide production was estimated by oxidation of phenol red, while the Griess reagent was used to determine the nitric oxide production. 1 and 4-methoxy-ethyl orsellinate (XVII) were the compounds that induced the greatest release of H2O2, whereas n-pentyl orsellinate (IV), iso-propyl orsellinate (V), sec-butyl orsellinate (VI), and XVII induced a small release of NO. These results indicate that lichen products and their derivatives have potential immune-modulating activities

Effects of endogenous antidiuretic hormone (ADH) on macrophage phagocytosis.

Although several studies have indicated that antidiuretic hormone (ADH) enhances the phagocytic function of the reticuloendothelial system (RES) in shock syndromes, it remains unknown what influence ADH exerts upon the individual phagocytic components of this system. The present investigation was designed to evaluate the effects of endogenous ADH on the phagocytic activity of peritoneal macrophage cells. As a phagocytic stimuli, fluorescent methacrylate microbeads were injected intraperitoneally into Brattleboro (ADH deficient) and normal Long Evans rats in the presence and absence of exogenous ADH. Peritoneal cells were harvested 19-22 hr after the administration of the microbeads and the percent phagocytosis was determined in macrophage cells using a fluorescence-activated cell sorter (FACS II). Our results indicate that the percentage of peritoneal macrophages ingesting the fluorescent methacrylate microbeads was significantly reduced in the absence of ADH (Brattleboro rats: 5.4 +/- 0.6% versus Long Evans rats: 16.8 +/- 2.3%; p less than 0.001). In addition, our data demonstrate that exogenous administration of ADH significantly enhanced macrophage phagocytosis in Brattleboro (14.7 +/- 2.2%) and normal Long Evans (49.6 +/- 4.5%) rats. These data suggest, for the first time, that endogenous ADH might play a modulatory role in the phagocytic activity of a specific component of the RES, namely, the macrophage cell.