Synthesis, design, and assessment of novel morpholine-derived Mannich bases as multifunctional agents for the potential enzyme inhibitory properties including docking study.

The synthesized Schiff Bases were reacted with formaldehyde and secondary amine such as 2,6-dimethylmorpholine to afford N-Mannich bases through the Mannich reaction. 3-Substitued-4-(4-hydroxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones (4) were treated with 2,6-dimethylmorpholine in the presence of formaldehyde to synthesize eight new 1-(2,6-dimethylmorpholino-4-yl-methyl)-3-substitued-4-(4-hydroxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones (4a-h). The structures of the synthesized eight new compounds were characterized using IR, 1H NMR, 13C NMR, and HR-MS spectroscopic methods. Synthesized compounds inhibitory activity determined against the acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and glutathione S-transferase (GST) enzymes with Ki values in the range 25.23-42.19 µM for AChE, 19.37-34.22 µM for BChE, and 21.84-41.14 µM for GST, respectively. Binding scores of most active inhibitors against AChE, BChE, and GST enzymes were detected as -10.294 kcal/mol, -9.562 kcal/mol, and -7.112 kcal/mol, respectively. The hydroxybenzylidene moiety of the most active inhibitors caused to inhibition of the enzymes through hydrophobic interaction and hydrogen bond.

Residual behavior and risk assessment of tridemorph in banana conditions.

An efficient method has been developed for determining tridemorph in banana using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The dissipation and terminal residue of tridemorph in banana fields were carried out at good agricultural practice (GAP) conditions. The average recoveries ranged from 84.4% to 90.0% with relative standard deviations (RSDs) of 3.0%-7.0% at three different spiking levels. The results indicated that the tridemorph dissipated quickly in banana with half-lives of 7.0-7.7days. The results of residual distribution ranged from 0.01 to 0.26mg/kg, 0.01-0.62mg/kg and <0.01mg/kg in whole banana, peel and pulp, respectively. The relationship between application factor and residue was discussed. The results of risk assessment showed that the risk quotient (RQ) value was all below RQ=1. Given that China has not set an maximum residue limit (MRL) value for tridemorph in banana, this study could provide guidance for the reasonable use of tridemorph.

A novel pre-treatment for the methane production from microalgae by using N-methylmorpholine-N-oxide (NMMO).

The aim of this work was to study the effect of the solvent N-methylmorpholine-N-oxide (NMMO) to pre-treat Nannochloropsis oculata before the anaerobic digestion process. The results indicated that the pre-treatment affects the characteristics of the cell wall, which consequently becomes more susceptible to the microorganisms attack during anaerobic digestion. The methane production was increased by 43% after the pre-treatment, from 238±6mLCH4/gVS until 339±4mLCH4/gVS. On the contrary, the methane production from Chlorella vulgaris decreased after the pre-treatment from 251±4mLCH4/gVS to 231±3mLCH4/gVS. The failure on the pre-treatment was attributed to the particular characteristics of the substrate in consequence of a previous drying step.

Stability-indicating methods for the determination of mosapride citrate in the presence of its degradation products according to ICH guidelines.

In the present work, different spectrophotometric methods and one spectrofluorimetric method have been developed and validated for the determination of mosapride citrate in the presence of its acid-induced degradation products. The drug was subjected to stress stability study including acid, alkali, oxidative, photolytic, and thermal stress degradation. The developed spectrophotometric methods included the use of first order derivative ((1)D), derivative of ratio spectra ((1)DD), mean centring of ratio spectra (MC) and H-point standard additions (HPSAM) spectrophotometric methods. For (1)D method, the peaks amplitudes at 282.8 and 319.6 nm were measured, while for (1)DD method those at 308 nm and 323 nm were measured. Mean centring of ratio spectra method used the values at 317 nm for calibration, while for HPSAM the absorbance at 273 and 288.6 nm were used. These methods were successfully applied for determination of mosapride in the concentration range of 5-70 µg.ml(-1). The spectrofluorimetric method was based on measuring the native fluorescence of mosapride in 0.1 M NaOH using λ(excitation) 276 nm and λ(emission) 344 nm and 684 nm with linearity ranges of 50-3000 ng.ml(-1) and 50-9000 ng.ml(-1), respectively. All the developed methods were validated according to the International Conference on Harmonization (ICH) guidelines and were applied for bulk powder and dosage form. The results obtained were statistically compared to each other using one-way ANOVA testing.

A combined approach to drug metabolism and toxicity assessment.

The challenge of predicting the metabolism or toxicity of a drug in humans has been approached using in vivo animal models, in vitro systems, high throughput genomics and proteomics methods, and, more recently, computational approaches. Understanding the complexity of biological systems requires a broader perspective rather than focusing on just one method in isolation for prediction. Multiple methods may therefore be necessary and combined for a more accurate prediction. In the field of drug metabolism and toxicology, we have seen the growth, in recent years, of computational quantitative structure-activity relationships (QSARs), as well as empirical data from microarrays. In the current study we have further developed a novel computational approach, MetaDrug, that 1) predicts metabolites for molecules based on their chemical structure, 2) predicts the activity of the original compound and its metabolites with various absorption, distribution, metabolism, excretion, and toxicity models, 3) incorporates the predictions with human cell signaling and metabolic pathways and networks, and 4) integrates networks and metabolites, with relevant toxicogenomic or other high throughput data. We have demonstrated the utility of such an approach using recently published data from in vitro metabolism and microarray studies for aprepitant, 2(S)-((3,5-bis(trifluoromethyl)benzyl)-oxy)-3(S)phenyl-4-((3-oxo-1,2,4-triazol-5-yl)methyl)morpholine (L-742694), trovofloxacin, 4-hydroxytamoxifen, and artemisinin and other artemisinin analogs to show the predicted interactions with cytochromes P450, pregnane X receptor, and P-glycoprotein, and the metabolites and the networks of genes that are affected. As a comparison, we used a second computational approach, MetaCore, to generate statistically significant gene networks with the available expression data. These case studies demonstrate the combination of QSARs and systems biology methods.

Fluorometric assessment of In vitro antidermatophytic activities of antimycotics based on their keratin-penetrating power.

Keratin particles impregnated with amorolfine or clotrimazole in serial doubling dilutions (64 to 0.125 microg/ml) were used to evaluate the activities of these agents against 20 isolates each of Trichophyton mentagrophytes and Trichophyton rubrum in a yeast carbon broth medium incorporating Alamar Blue dye. The proposed MIC with keratin impregnation (MIC(K)) is defined as the lowest concentration of an agent used to impregnate keratin particles that effects a fluorescence-based fungal growth quotient of 0.05 or less. The conventional colorimetric and visual MICs of amorolfine for the dermatophytes, 64 microg/ml] and 64 microg/ml [range, 16 to >64 microg], respectively) may indicate the strong in vivo antidermatophytic activity of amorolfine as a topical agent. The new antidermatophytic susceptibility testing procedure has potential clinical utility for the in vitro screening of agents for use in the topical treatment of superficial mycoses.