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.     

Enhanced h6h transcript level,antioxidant activity and tropane alkaloid production in Hyoscyamus reticulatus L. hairy roots elicited by acetylsalicylic acid

Hyoscyamine (Hyos) and scopolamine (SCP) are drugs widely used as antimuscarinic to treat diseases such as Parkinson’s or to calm schizoid patients. In this study, with the aim of enhancing tropane alkaloid production in H. reticulatus hairy root cultures, the effects of the signalling molecule acetylsalicylic acid (ASA) were investigated at different concentrations (0, 0.01, 0.1 and 1 mM) and inoculation times (24 and 48 h). As well as reducing biomass production, ASA treatment significantly enhanced the activity of catalase, guaiacol peroxidase and ascorbate peroxidase (p < 0.01), which was highest at 48 h of exposure to 1 mM of ASA. The highest accumulation of Hyos and SCP (1.6- and 3.5-fold more than in the control, respectively) was obtained at 24 h of exposure to 0.1 mM ASA. Additionally, semi-quantitative RT-PCR analysis showed an increased expression of the hyoscyamine-6-beta-hydroxylase (h6h) gene, involved in the last Hyos and SCP biosynthetic step, which correlated with the enhanced level of Hyos and SCP production under ASA elicitation. Our findings suggest that ASA, by stimulating the expression of key biosynthetic genes and enzymes, can be applied to increase commercial tropane alkaloid production in a H. reticulatus hairy root system.     

Design,synthesis and SAR studies of 4-allyoxyaniline amides as potent 15-lipoxygensae inhibitors

A group of 4-allyloxyaniline amides 5a–o were designed, synthesized and evaluated as potential inhibitors of soybean 15-lipoxygenase (SLO) on the basis of eugenol and esteragol structures. Compound 5e showed the best IC₅₀ in SLO inhibition (IC₅₀ = 0.67 ± 0.06 μM). All compounds were docked in SLO active site retrieved from RCSB Protein Data Bank (PDB entry: 1IK3) and showed that allyloxy group of compounds is oriented towards the Fe³⁺-OH moiety in the active site of enzyme and fixed by hydrogen bonding with two conserved His⁵¹³ and Gln⁷¹⁶. It is resulted that molecular volume of the amide moiety would be a major factor in inhibitory potency variation of the synthetic amides, where the hydrogen bonding of the amide group could also involve in the activity of the inhibitors.     

CFD simulation of mass transfer and flow behaviour around a single particle in bioleaching process

The pathway to reach a certain target in many processes such as bioleaching, due to the complex and poorly understood hydrodynamics, reaction kinetics, and chemistry knowledge involved is not apparent. An investigation of the interactions between the parameters in bioleaching process can be applied to optimize the rate of metal extraction from sulphide minerals. Such investigations can be carried out with the aid of numerical simulations. In this study, a computational fluid dynamics (CFD) model was developed to better understand the mass transfer phenomenon and complex flow field around a single particle. The commercial software FLUENT 6.2 has been employed to solve the governing equations. Volume of fluid (VOF) method was used to predict the fluid volume fraction in a 3D geometry. The computational model has successfully captured the results observed in the experiments. Simulation results indicate that concentrations of species in a thin layer of liquid on the particle surface are much higher than their concentrations in the liquid bulk and significant gradients in the ion concentrations between the surface of the particle and the liquid bulk were observed.     

Phytochemicals,Essential Oils Composition and Antioxidant Activity of Astragalus spp., Phlomis olivieri and Daphne mucronata in Habitats of Central Iran

This study evaluated several secondary metabolites, essential oils (EOs) compositions, and antioxidant activity in four medicinal plants that originated in Isfahan rangelands. The species were Astragalus verus, Astragalus adscendens, Daphne mucronata, and Phlomis olivieri. Thirty-two genotypes of these species were evaluated for different biochemical traits. Based on the evaluation of EOs compounds, GC/MS analysis revealed the total number of identified compounds. These compounds were 25, 22, 12, and 22 for A. adscendens, A. verus, D. mucronata, and P. olivieri, respectively. The dominant compounds were phthalate (59.88 %) in A. adscendens, phytol (38.02 %) in A. verus, hexanoic acid (32.05 %) in D. mucronata and β-cubebene (30.94 %) in P. olivieri. Phytochemical analysis showed that D. mucronata, A. adscendens, and P. olivieri had the highest total phenolics content (TPC) (18.24 mg gallic acid equivalent/g dry weight), total flavonoids content (5.57 mg QE/g DW), and total anthocyanins content (0.23 mg/g DW), respectively. The highest total chlorophyll (0.27 mg/g DW), total carotenoids (0.03 mg/g DW), and antioxidant activity (71.36 %) were observed in A. adscendens, A. adscendens and A. verus, respectively. Among all genotypes, the highest TPC (20.1 mg GAE/g DW) was observed in genotype 5 of D. mucronata. This study provided new information on the chemical compounds within the distribution range of these ecologically dominant rangeland species in Isfahan province, Iran. The data revealed that superior genotypes from these species are rich in natural antioxidants and bioactive compounds. Thus, they can be used in ethno pharmacological fields, food, and industrial applications.     

A family of acetylcholine-gated chloride channel subunits in Caenorhabditis elegans

The genome of the nematode Caenorhabditis elegans encodes a surprisingly large and diverse superfamily of genes encoding Cys loop ligand-gated ion channels. Here we report the first cloning, expression, and pharmacological characterization of members of a family of anion-selective acetylcholine receptor subunits. Two subunits, ACC-1 and ACC-2, form homomeric channels for which acetylcholine and arecoline, but not nicotine, are efficient agonists. These channels are blocked by d-tubocurarine but not by alpha-bungarotoxin. We provide evidence that two additional subunits, ACC-3 and ACC-4, interact with ACC-1 and ACC-2. The acetylcholine-binding domain of these channels appears to have diverged substantially from the acetylcholine-binding domain of nicotinic receptors.     

Activity and function in lung injuries due to sulphur mustard

Aim. Pulmonary complications are known to occur in over half the patients exposed to sulphur mustard. Many studies have focused on the clinical complications, often ignoring the pathogenesis of sulphur mustard. Also, the reasons for the variable severity of lung injuries caused by sulphur mustard are unclear. Hence, the current study was performed to evaluate the correlation between superoxide dismutase (SOD) and catalase (CAT) activity and pulmonary function in patients exposed to sulphur mustard. Methods. Our study was a comparative cross-sectional survey. Two hundred and fifty incident survivors were selected from the Sardasht population who were exposed to sulphur mustard in 1987. A control group from non-exposed civilians was also selected. We used a pulmonary function test, and SOD and CAT activity was measured in these groups. Results. The mean SOD activity in the healthy control group (70.5±10.8 U ml^?1) was higher than in the moderate-to-severe group (67.0±6.1 U ml^?1) (p <0.001, one-tail ANOVA, least significant difference (LSD) post hoc). The mean activity in the mild group (72.5±6.9 U ml^?1) was no higher than in the healthy control group (70.5±10.8 U ml^?1) (p=0.095 one-tail ANOVA, LSD post hoc). The mean CAT activity in the healthy control group (4.9±1.5 U ml^?1) was lower than in the moderate-to-severe group (8.0±1.8 U ml^?1) (p <0.001, one-tail ANOVA, LSD post hoc) and in the mild group (7.5±1.5 U ml^?1) (p=0.012 one-tail ANOVA, LSD post hoc). Conclusion. According to our findings, it is reasonable to hypothesize that re-establishment of the activation–inactivation or oxidant–antioxidant balance in favour of the activation and antioxidant balances would be useful as a therapeutic strategy to suppress pathological mechanisms underlying lung injuries.