How the chemical structure of phosphoramides affect the fire retardancy and mechanical properties of polylactide?

Phosphoramides, as a kind of high-efficient fire retardants, have been designed in many structures and endowed exceptional fire retardancy to polylactide (PLA). However, due to ignorance of the structure-property correlation, the effect of phosphoramides' structure on the fire retardancy and mechanical properties of PLA is still unclear. Herein, a series of biobased phosphoramides (phosphoramide (V1), linear polyphosphoramide (V2) and hyperbranched polyphosphamide (V3)) were designed and incorporated into PLA, and the structural effect of phosphoramides on the fire-retardant and mechanical properties of PLA was deeply researched. Among three kinds of phosphoramides, the hyperbranched polyphosphoramide is more effective than the corresponding linear polyphosphoramide and phosphoramide in improving the fire-retardant and anti-dripping properties of PLA, and only linear polyphosphoramide shows a positive effect in the mechanical strength of PLA. This work provides a feasible strategy for creating mechanically robust and fire-retardant polymer composites by molecularly tailoring the structure of fire retardants and uncovering their structure-property relationship.

Design, synthesis, and biological activity evaluation of 2-(benzo[b]thiophen-2-yl)-4-phenyl-4,5-dihydrooxazole derivatives as broad-spectrum antifungal agents.

To discover antifungal compounds with broad-spectrum and stable metabolism, a series of 2-(benzo[b]thiophen-2-yl)-4-phenyl-4,5-dihydrooxazole derivatives was designed and synthesized. Compounds A30-A34 exhibited excellent broad-spectrum antifungal activity against Candida albicans with MIC values in the range of 0.03-0.5 µg/mL, and against Cryptococcus neoformans and Aspergillus fumigatus with MIC values in the range of 0.25-2 µg/mL. In addition, compounds A31 and A33 showed high metabolic stability in human liver microsomes in vitro, with the half-life of 80.5 min and 69.4 min, respectively. Moreover, compounds A31 and A33 showed weak or almost no inhibitory effect on the CYP3A4 and CYP2D6. The pharmacokinetic evaluation in SD rats showed that compound A31 had suitable pharmacokinetic properties and was worthy of further study.

Improving the metabolic stability of antifungal compounds based on a scaffold hopping strategy: Design, synthesis, and structure-activity relationship studies of dihydrooxazole derivatives.

l-amino alcohol derivatives exhibited high antifungal activity, but the metabolic stability of human liver microsomes in vitro was poor, and the half-life of optimal compound 5 was less than 5 min. To improve the metabolic properties of the compounds, the scaffold hopping strategy was adopted and a series of antifungal compounds with a dihydrooxazole scaffold was designed and synthesized. Compounds A33-A38 substituted with 4-phenyl group on dihydrooxazole ring exhibited excellent antifungal activities against C. albicans, C. tropicalis and C. krusei, with MIC values in the range of 0.03-0.25 µg/mL. In addition, the metabolic stability of compounds A33 and A34 in human liver microsomes in vitro was improved significantly, with the half-life greater than 145 min and the half-life of 59.1 min, respectively. Moreover, pharmacokinetic studies in SD rats showed that A33 exhibited favourable pharmacokinetic properties, with a bioavailability of 77.69%, and half-life (intravenous administration) of 9.35 h, indicating that A33 is worthy of further study.

Long-term trends in water quality and influence of water recharge and climate on the water quality of brackish-water lakes: A case study of Shahu Lake.

This study aimed to assess the long-term fluctuations in water quality and the influence of Yellow River water recharge and climatic condition on the water environmental index of a typical brackish-water lake. This study investigated several surface water quality parameters and their relationships with the water quality index (WQI) and trophic status index (TSI) of Shahu Lake from 2011 to 2018. A health risk assessment was conducted, and the correlations among water recharge, climatic conditions, and the aforementioned elements were determined. Results show that the water quality in this lake went from good to moderate and back to good as reflected in the changes in its WQI values from 2011 to 2018. The relative water quality inferiority of this lake in 2015 and 2016 was attributed to the significant increase in its CODMn, TP, TN, NH3-N, and fluoride (F-) concentrations during these years. A combination of these parameters could rapidly predict water quality through a stepwise multiple linear regression. During the study period (except in the frozen season), Shahu Lake maintained a eutrophic status every month (especially in July) irrespective of the spatial changes resulting from low secchi depth and high TP. The limiting nutrient of Shahu Lake changed from phosphorus to both nitrogen and phosphorus, especially during summer, due to seasonal variations and exogenous inputs. The lake had an acceptable health risk level, and water recharge both had positive and negative effects on this lake as reflected in the significant decrease or increase in the concentrations of its principal parameters. This condition was also attributed to temperature and precipitation, which resulted in significant TSI variations. The findings of this study provide ways of estimating and forecasting water quality and trophic status and a basis for managing and improving similar brackish-water lakes.

Combating fluconazole-resistant fungi with novel ß-azole-phenylacetone derivatives.

A series of ß-azole-phenylacetone derivatives with novel structures were designed and synthesized to combat the increasing incidence of susceptible fungal infections and drug-resistant fungal infections. The antifungal activity of the synthesized compounds was assessed against five susceptible strains and five fluconazole-resistant strains. Antifungal activity tests showed that most of the compounds exhibited excellent antifungal activities against five pathogenic strains with MIC values in the range of 0.03-1 µg/mL. Compounds with R1 = 3-F substituted and 15o and 15ae exhibited moderate antifungal activities against fluconazole-resistant strains 17# and CaR with MIC values in the range of 1-8 µg/mL. Compounds with R1 = H or 2-F (such as 15a, 15o, 15p) displayed moderate to good antifungal activity against fluconazole-resistant strains 632, 901 and 904 with MIC values in the range of 0.125-4 µg/mL. Notably, 15o and 15ae exhibited antifungal activity against five susceptible strains and five fluconazole-resistant strains. Preliminary mechanistic studies showed that the potent antifungal activity of compound 15ae stemmed from inhibition of C. albicans CYP51. Compounds 15o, 15z and 15ae were nearly nontoxic to mammalian A549 cells.

Strategies for the development of highly selective cytochrome P450 inhibitors: Several CYP targets in current research.

Cytochromes P450 (CYPs) play an important role in the metabolism of endogenic and xenobiotic substances, especially drugs. In addition, many CYPs may serve as targets for disease treatment. However, due to the presence of a common heme, the hydrophobicity of the CYP binding cavity, and the high homology within the binding pocket, most CYP inhibitors lack selectivity, which often leads to drug-drug interactions. Therefore, it is meaningful to develop highly selective CYP inhibitors. In this review, we summarize some of the strategies that have been used to develop highly selective CYP inhibitors, such as the weakening of the heme-binding group interaction, reduction of molecular lipophilicity and introduction of small structural changes within compounds.

Design, synthesis, and structure-activity relationship studies of l-amino alcohol derivatives as broad-spectrum antifungal agents.

To discover broad spectrum antifungal agents, two strategies were applied, and a novel class of l-amino alcohol derivatives were designed and synthesized. 3-F substituted compounds 14i, 14n, 14s and 14v exhibited excellent antifungal activities with broad antifungal spectra against C. albicans and C. tropicalis, with MIC values in the range of 0.03-0.06 µg/mL, and against A. fumigatus and C. neoformans, with MIC values in the range of 1-2 µg/mL. Notably, Compounds 14i, 14n, 14s and 14v also displayed moderate activities against fluconazole-resistance strains 17# and CaR that were isolated from AIDS patients. Moreover, only compounds in the S-configuration showed antifungal activity. Preliminary mechanistic studies showed that the potent antifungal activity of compound 14v stemmed from inhibition of C. albicans CYP51. Compounds 14n and 14v were almost nontoxic to mammalian A549 cells, and their stability in human plasma was excellent.