First-in-human trial of SAR107375E, a novel small molecule anticoagulant with dual inhibition of factor Xa and factor IIa.

BACKGROUND: SAR107375E is a direct dual inhibitor of both Factor Xa and Factor IIa and has shown potent anticoagulation activity in vitro and animals. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending intravenous doses of SAR107375E in healthy Chinese adult subjects. METHODS: In this randomized, double-blind, placebo-controlled trial, 60 healthy Chinese adult subjects were administered intravenously single ascending doses (0.5, 1.5, 3.0, 5.0, 7.5, 10.0, 15.0, or 20.0 mg) of SAR107375E (N = 44) or placebo (N = 16). Plasma and urine concentrations of SAR107375E were measured and used to calculate pharmacokinetic parameters. Coagulation functions were measured and compared with baseline values. Treatment-emergent adverse events were recorded to evaluate safety. RESULTS: In plasma, from the 0.5 to 20.0 mg dose group, t1/2 is 1.51-4.00 h, Cmax is 59.05-1360 ug/L, and AUC0-t is 25.01-528.45 h*ug/L. And it shows dose proportionality in the 5.0-20.0 mg range. Activated partial thromboplastin time and Ecarin clotting time correlated linearly with drug plasma concentration. No serious adverse events were reported during the study. CONCLUSION: SAR107375E exhibits good safety and tolerability, predictable pharmacokinetics and pharmacodynamics. CLINICAL TRIAL REGISTRATION: www.chinadrugtrials.org.cn, identifier is CTR20211082.

Zero-valent iron is not always effective in enhancing anaerobic digestion performance.

Liquid nitrogen was employed as a low-temperature medium to activate zero-valent iron (ZVI) powder in an attempt to strengthen its enhancement effect on anaerobic digestion (AD) of swine manure (SM). Surprisingly, it was found that both pristine ZVI and liquid nitrogen-pretreated ZVI (LZVI) did not significantly improve the AD performance or change the archaeal community structure. It was hypothesized that ZVI might not be effective at stress-free environment like in these digesters. To confirm this, an additional set of AD experiments were performed at high ammonia stress (about 4000 mg/L), results showed that ZVI and LZVI greatly alleviated ammonia inhibition and increased the CH4 yield by 11.6% and 28.2%, respectively. Apparently, ZVI mainly affected AD systems by changing the metabolism pathways and enhancing the microbial activity to overcome process inhibition, and pretreatment of liquid nitrogen could significantly accelerate the dissolution of ZVI and improve its utilization efficiency, contributing to a greater extend of process recovery and improvement.

A series of octahydroquinazoline-5-ones as novel inhibitors against dengue virus.

A series of octahydroquinazoline-5-ones (OHQs 1-50) were designed and synthesized via an improved five-component reaction (5CR). Their bioactivities against dengue virus (DENV) were evaluated by determining lacate dehydrogenase (LDH) in the BHK-21 cells infected with DENV-2. Primary structure-activity relationship showed that six of OHQs with suitable substituents displayed good activities with EC50 = 1.31-1.85 µM. The primary bioactivity mechanism was investigated using the most potent OHQ 23. Experimental results indicate that 23 could efficiently reverse the DENV-2-induced cytopathic effect and suppress the expression of viral structure E protein, but showed no interaction with the MTase and RdRp domain of NS5, a protein plays an important role in viral genome transcription and viral protein translation. The efficient synthetic method, novel structures as DENV inhibitors and good activities are expected to be developed potential DENV inhibitors.

Design, synthesis and antibacterial evaluation of 2,4-disubstituted-6-thiophenyl-pyrimidines.

The increasing incidences of multidrug resistant bacterial infections urge the development of novel antibacterial having a new mechanism of action. The small molecule-based inhibitors targeting at the cell division protein FtsZ has been recognized as a promising approach to search for new antibacterial with high potency. In the present study, a series of novel 2,4-disubstituted-6-thiophenyl-pyrimidine derivatives were synthesized and their antibacterial activities against clinically related pathogens were investigated. The compounds show strong antibacterial activities against MRSA and VREs. The antibacterial activity of compound Bb2 against MRSA and VREs (MIC values: 2 µg/mL) is stronger than that of methicillin and vancomycin. From the in vitro and in vivo results, Bb2 was found to inhibit GTPase activity and FtsZ polymerization. The compound is able to inhibit bacterial cell division through interacting with GTP binding site of FtsZ and thus causing cell death. In addition, S. aureus was found to develop resistance to methicillin but not for Bb2, which was proved in our resistance generation experiments.

Effect of oral nut supplementation on endothelium-dependent vasodilation - a meta-analysis.

BACKGROUND: An inverse association was found between nut supplementation and the risk of cardiovascular disease. Identifying the direct effect of nut supplementation on endothelium-dependent vasodilation may partly explain that association. METHODS: Human intervention studies were identified by systematic electronic search of the databases EMBASE, MEDLINE, Pubmed, and Web of Science through January 2017 and by manually searching related articles. Subgroup analyses were performed to identify the source of heterogeneity among studies. RESULTS: In total, 11 eligible articles involving 468 participants were included in the meta-analysis. Overall, the results of the 13 trials showed that nut supplementation significantly increased flow-mediated dilation [weighted mean differences (WMD): 1.03 %; 95 % CI: 0.26-1.79 %, P = 0.008]. There was significant heterogeneity among studies (P = 0.006) that might partly be explained by the different types of nuts. No significant association between nut supplementation and endothelium-independent vasodilatation was observed in a fixed effect model (WMD: 1.10 %, 95 % CI: -0.19-2.38 %, P = 0.09). CONCLUSIONS: Supplementation of nuts significantly improves the vascular endothelial function without affecting endothelium-independent vasodilatation.

A hydrophobic organelle probe based on aggregation-induced emission: Nanosuspension preparation and direct use for endoplasmic reticulum imaging in living cells.

Organic fluorophores have a wide range of biological uses and are usually needed to be prepared as water-soluble compounds or nanoparticles for applications in aqueous biosystems owing to their hydrophobic properties, which often is a complex, time-consuming and high-cost process. Here, the nanoparticle preparation of hydrophobic fluorophores and their application in cell imaging have been investigated. It was found: a) fetal bovine serum (FBS) shows an excellent dispersion effect on hydrophobic small-molecule organic compounds; b) a hydrophobic C6-unsubstituted tetrahydropyrimidine (Me-THP-Naph) can be prepared as nanosuspensions utilizing cell culture medium with 10% FBS and directly be used as a specific real-time imaging probe for the endoplasmic reticulum (ER), a dynamic organelle playing a crucial role in many cellular processes. Compared with existing ER-targeted organic fluorescent probes, Me-THP-Naph, a product of an efficient five-component reaction that we developed, has unconventional aggregation-induced emission characteristics and shows advantages of low cost, long-term staining, good photostability, high signal-to-noise ratio and excellent biocompatibility, which make it a potential specific probe for real-time ER imaging. More importantly, this work affords a simple strategy for direct application of hydrophobic organic compounds in aqueous biological systems.

Moderate alcohol consumption and atherosclerosis : Meta-analysis of effects on lipids and inflammation.

OBJECTIVE: Alcohol consumption plays an important role in the risk of major cardiovascular diseases. We conducted a meta-analysis to summarize the association between moderate alcohol consumption and atherosclerosis. DESIGN: In this study four databases and reference lists of retrieved articles were searched to identify eligible studies. A meta-analysis was carried out of all interventional studies that assessed the effects of moderate alcohol consumption on concentrations of low density lipoprotein cholesterol, high density lipoprotein cholesterol, triglycerides, apolipoprotein A I, interleukin 6, plasminogen activator inhibitor 1, fibrinogen, and other biomarkers previously found to be associated with risk of atherosclerosis. RESULTS: A total of 31 studies met the eligibility criteria. In response to moderate alcohol consumption, low density lipoprotein cholesterol decreased by 0.08 mmol/l (P = 0.05), and high density lipoprotein cholesterol increased by 0.08 mmol/l (P < 0.00001), whereas total cholesterol and triglyceride remained the same. Moreover, interleukin 6 decreased by 0.43 pg/ml (P = 0.03), whereas C­reactive protein and tumor necrosis factor a remained the same. Several hemostatic factors and adiponectin were modestly affected by alcohol consumption. CONCLUSION: Moderate alcohol consumption is causally related to lower risk of atherosclerosis through changes in lipid profiles and inflammation.

Efficient Synthesis of a Series of Novel Octahydroquinazoline-5-ones via a Simple on-Water Urea-Catalyzed Chemoselective Five-Component Reaction.

Multicomponent reactions (MCRs) have become a powerful tool for drug discovery and development owing to their advantages of fast and efficient construction of a large library of products with complexity and diversity. However, conventional MCRs usually proceed in environmentally unfriendly organic solvents rather than in water, a green solvent used by nature for biological chemistry. Herein, a simple and efficient on-water urea-catalyzed chemoselective five-component reaction (5CR) has been developed for the synthesis of a series of novel octahydroquinazoline-5-ones (6), the derivatives of quinazolinones possessing diverse biological activities. The molecular structure of 6{1,1,12} has been confirmed by single-crystal X-ray diffraction. The 5CR can proceed at room temperature under normal atmospheric pressure in good yields and afford a large library of octahydroquinazoline-5-ones with various aromatic and aliphatic substituents at N-1, C-2, and N-3. In addition, a green method has been developed for the synthesis of enaminones, important intermediates in the 5CR and in synthetic chemistry.

Development of four-component synthesis of tetra- and pentasubstituted polyfunctional dihydropyrroles: free permutation and combination of aromatic and aliphatic amines.

We previously reported the novel efficient proton/heat-promoted four-component reactions (4CRs) of but-2-ynedioates, two same/different primary amines, and aldehydes for the synthesis of tetra- and pentasubstituted polyfunctional dihydropyrroles. If aromatic and aliphatic amines were used as reagents, four different series of products should be obtained via the permutation and combination of aromatic and aliphatic primary amines. However, only three/two rather four different series of tetra-/pentasubstisuted dihydropyrroles could be prepared via the proton/heat-promoted 4CRs. Herein, Cu(OAc)2·H2O, a Lewis acid being stable in air and water, was found to be an efficient catalyst for the 4CR synthesis of all the four different series of tetra-/pentasubstisuted dihydropyrroles. The copper-catalyzed 4CR could produce target products at room temperature in good to excellent yields. Interestingly, benzaldehyde, in addition to being used as a useful reactant for the synthesis of pentasubstituted dihydropyrroles, was found to be an excellent additive for preventing the oxidation of aromatic amines with copper(II) and ensuring the sooth conduct of the 4CRs for the synthesis of tetrasubstituted dihydropyrroles with aryl R(3). In addition, salicylic acid was found to be needed to increase the activities and yields of the copper-catalyzed 4CRs for the synthesis of petasubstituted diyhydropyrroles. On the basis of experimental results, the enamination/amidation/intramolecular cyclization mechanism was proposed and amidation is expected to be the rate-limited step in the copper-catalyzed 4CRs.

A new series of C-6 unsubstituted tetrahydropyrimidines: convenient one-pot chemoselective synthesis, aggregation-induced and size-independent emission characteristics.

A new series of C-6 unsubstituted tetrahydropyrimidines 6 have been directly synthesized via a convenient urea-catalyzed chemoselective five-component reaction (5CR) under mild conditions. Compounds 6 show typical aggregation-induced emission enhancement (AIEE) characteristics because they are practically no emissive in solution but emit blue or green fluorescence in aggregates with fluorescence yield up to 93%. One of the 5CR products, 6aa, exhibits blue- and green-fluorescence aggregates (bf- and gf-aggregates). The bf- and gf-aggregates are prepared under different conditions and proved to result from different J-aggregations by single-crystal X-ray analysis. In addition, the bf- and gf-aggregates of 6aa show unusual size-independent emission (SIE) characteristics because their maximum emission wavelengths in different sizes (suspension particles, film, powder and crystals) are the same, 434 and 484 nm, respectively. Based on the obtained experimental results, the 5CR mechanism, the origins of AIEE and SIE characteristics are discussed.

A novel class of small-molecule caspase-3 inhibitors prepared by multicomponent reactions.

A series of tetra- and pentasubstituted polyfunctional dihydropyrroles 5 and 6 were synthesized via practical multicomponent reactions (MCRs) for research on their structure-activity relationship as caspase-3 inhibitors. Among 39 compounds evaluated, 14 of them exhibited inhibition against caspase-3 with IC(50) ranging from 5 to 20 µM. The inhibitory activities of 5 and 6 depend on the nature of substituents on different positions. 5 and 6 possess a different scaffold from those previously reported and are the first caspase-3 inhibitors prepared via MCRs. The most active compounds 5k (IC(50) = 5.27 µM) could therefore be used as a lead for the development of highly potent caspase-3 inhibitors as drug candidates for therapeutic agents by taking advantage of MCRs.