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An unprecedented cross-coupling reaction of alkyl carbagermatranes with bromofluoroolefins to deliver dialkyl-substituted monofluoroalkenes was achieved. This cross-coupling reaction was performed under base/additive-free conditions with excellent functional group tolerance, therefore offering an opportunity for challenging dialkyl-substituted monofluoroalkenes. The preparation of bioactive agent analogues including an antitubercular agent mimic and a COX-2 inhibitor analogue and the late-stage fluoroalkenylation of drug-molecule derivatives proved the utility of this strategy.

BackgroundPast studies have found a strong relationship between alcohol drinking and human health.MethodsIn this study, we first tested the association of rs671 with alcohol use in 2349 participants in southeast China. We then evaluated the causal impact between alcohol use and cardiovascular traits through a Mendelian randomisation (MR) analysis.ResultsWe found strong evidence for the association of rs671 in the ALDH2 gene with alcohol drinking (p=6.08×10-47; ORadj G=4.50, 95% CI 3.67 to 5.52). We found that female G carriers of rs671 had a higher proportion of non-drinkers than male G carriers (88.01% vs 38.70%). In non-drinkers, the female G allele frequency was higher than the male G allele frequency (71.1% vs 55.2%). MR analysis suggested that alcohol use had a causal effect on blood pressure (increasing 9.46 mm Hg for systolic blood pressure (p=9.67×10-4) and 7.50 mm Hg for diastolic blood pressure (p=9.62×10-5)), and on hypertension in men (p=0.011; OR =1.19, 95% CI 1.04 to 1.36) and in pooled samples (p=0.013; OR =1.20, 95% CI 1.04 to 1.39), but not in women. We did not observe a causal effect of alcohol use on body mass index and lipid levels; further studies are needed to clarify the non-causal relationship.ConclusionsCompared to never-drinkers, current and previous alcohol use had a causal effect on blood pressure and hypertension in pooled samples and in men. These results reflect Chinese culture which does not encourage women to drink.

BACKGOUND Acetohydroxyacid synthase (AHAS; EC 2.2.1.6) is the first common enzyme in the biosynthetic pathway leading to the branched-chain amino acids in plants and a wide range of microorganisms. With the long-term and wide application of AHAS inhibitors, weed resistance is becoming a global problem, which leads to an urgent demand for novel inhibitors to antagonize both wild-type and resistant AHAS. RESULTS Pyrimidinyl-Salicylic acid derivatives, as one of the main classes of commercial AHAS herbicides, show potential anti-resistant bioactivity to wild-type and P197L mutant. In current work, a series of novel 2-benzoyloxy- 6-pyrimidinyl salicylic acid derivatives were designed through fragment-based drug discovery (FBDD). Fortunately, the newly synthesized compounds showed a good inhibitory activity against both wild-type and P197L mutant. Some compounds not only had a lower resistance factor value, but also showed an excellent inhibitory activity against wild type AHAS and P197L mutant. Furthermore greenhouse experiments showed compound 11 m displayed almost 100% inhibition against both wild-type and high-resistant Descurainia sophia at the dosage of 150 g.ai/ha. CONCLUSION The present work indicated that the 2-benzoyloxy- 6-pyrimidinyl salicylic acid motif was well worth further optimization. And compound 11 m can be used as a potential anti-resistant AHAS herbicide which requires further research.

Acetohydroxyacid synthase (AHAS; also known as acetolactate synthase; EC 2.2.1.6, formerly EC 4.1.3.18) is the first common enzyme in the biosynthetic pathway leading to the branched-chain amino acids in plants and a wide range of microorganisms. Weed resistance to AHAS-inhibiting herbicides, increasing at an exponential rate, is becoming a global problem and leading to an urgent demand of developing novel compounds against both resistant and wild AHAS. In the present work, a series of novel 2-aroxyl-1,2,4-triazolopyrimidine derivatives (a total of 55) were designed and synthesized with the aim to discover an antiresistant lead compound. Fortunately, the screening results indicated that many of the newly synthesized compounds showed a better, even excellent, inhibition effect against both the wild-type Arabidopsis thaliana AHAS and P197L mutants. Among them, compounds 5-3 to 5-17, compounds 5-19 to 5-26, compounds 5-28 to 5-45, and compound 5-48 have the lower values of resistance factor (RF) and display a potential power to overcome resistance associated with the P197L mutation in the enzyme levels. Further greenhouse in vivo assay showed that compounds 5-15 and 5-20 displayed "moderate" to "good" herbicidal activity against both the wild type-and the resistant (P197L mutation) Descurainia sophia, even at a rate as low as 0.9375 (g of ai/ha). The above results indicated that these two compounds could be used as new leads for the future development of antiresistance herbicides.

As an important fragment and synthetic intermediate, functionalized 6-arylsalicylate substructure widely exist in pharmacologically relevant natural products and bioactive compounds. In our recent works, we discovered two highly potent inhibitors for combating mutants of acetohydroxyacid synthase (AHAS), an important target for herbicide discovery. These two inhibitors contain 6-arylsalicylate skeleton. Previously, we have explored a new method to synthesize position-6 aryl substituted salicylic acid fragment. However, this method failed to synthesize 4-methyl-6-aryl salicylic acids. Herein, we developed a new efficient method for the synthesis of functionalized 4-methyl-6-bulkyarylsalicylates via a microwave-promoted Suzuki cross-coupling. This method has obvious advantages, such as a wide range of substrates, smooth and rapid reaction, moderate to excellent yields. Due to its superiority to the traditional available methods, this protocol could be utilized to synthesize pyrimidinyl(thio)salicylic acid and its derivatives.

The issue of weed resistance to acetohydroxyacid synthase (EC 2.2.1.6, AHAS) inhibitors has become one of the largest obstacles for the application of this class of herbicides. In a continuing effort to discover novel AHAS inhibitors to overcome weed resistance, a series of pyrimidine–biphenyl hybrids (4aa–bb and 5aa–ah) were designed and synthesized via a scaffold hopping strategy. Among these derivatives, compounds 4aa (Ki = 0.09 μM) and 4bb (Ki = 0.02 μM) displayed higher inhibitory activities against Arabidopsis thaliana AHAS than those of the controls bispyribac (Ki = 0.54 μM) and flumetsulam (Ki = 0.38 μM). Remarkably, compounds 4aa, 4bb, 5ah, and 5ag exhibited excellent postemergence herbicidal activity and a broad spectrum of weed control at application rates of 37.5–150 g of active ingredient (ai)/ha. Furthermore, 4aa and 4bb showed higher herbicidal activity against AHAS inhibitor-resistant Descurainia sophia, Ammannia arenaria, and the corresponding sensitive weeds than that of bispyribac at 0....

Isatin (1H-indole-2,3-dione, ) was first obtained by Erdman and Laurent in 1841 as a product from the oxidation of indigo by nitric and chromic acids.1 Since then, isatin and its derivatives have b...

Functionalized 6-substituted-thiosalicylates are key intermediates for the synthesis of pyrimidinyl(thio)salicylic acids, a group of important herbicides targeting plant acetohydroxyacid synthase. Therefore, it is of great interest to develop an efficient method for the syntheses of 6-substituted-thiosalicylates. Herein, we have developed a direct and efficient method for the synthesis of functionalized 6-substituted-thiosalicylates (4) from aryl iodide (1) by using an improved microwave-assisted Suzuki cross-coupling reaction. Almost all the reactions proceeded smoothly and afforded moderate to excellent yields of products. Moreover, this protocol is obviously superior to the traditional available methods and could be utilized to synthesize pyrimidinyl(thio)salicylic acid and its derivatives.

Functionalized 6-arylsalicylate substructures occur in a variety of pharmacologically relevant natural products and bioactive compounds. They are also broadly used as important intermediates in organic synthesis. Traditional synthetic methods have suffered from some drawbacks, such as relatively harsh reaction conditions, narrow range of substrates, and poor yields. Utilizing microwave irradiation, the synthesis of functionalized 6-arylsalicylates via a Suzuki cross-coupling has been developed with a wide range of substrates. Almost all the reactions proceeded smoothly and afforded moderate to excellent yields of products, which indicated that electronic effects and steric modifications have little effect on this reaction.

Functionalized 6-arylsalicylate substructures occur in a variety of pharmacologically relevant natural products and bioactive compounds. Especially 6-arylsubstituted salicylates, as a key pharmacophore of anti-resistant acetohydroxyacid synthase (AHAS) inhibitors have played a lead role in combatting the weed-resistance issues. Previously, we have explored two new methods to synthesize position-6 aryl substituted salicylic acid fragment. However, these two methods failed to introduce various substituents into salicylic acid. Here an efficient method for the synthesis of 6-substituted salicylates is described via a microwave-promoted Suzuki cross-coupling. Due to the obvious advantages of this method, such as a wide range of substrates, smooth and rapid reaction and moderate to excellent yields, this protocol could be utilized to synthesize more anti-resistant AHAS inhibitors.

Isatin (1H-indole-2,3-dione, ) was first obtained by Erdman and Laurent in 1841 as a product from the oxidation of indigo by nitric and chromic acids.1 Since then, isatin and its derivatives have b...

The improved microwave assisted Suzuki cross-coupling of aryl iodides (I) with boronic acids followed by deprotection produces various thiosalicylates.

Electronic and steric modifications have only small effects on the reactions of 4-iodoisatins with aryl- and alkenyl boronic acids.

NG2 cells, a fourth type of glial cell in the mammalian CNS, undergo reactive changes in response to a wide variety of brain insults. Recent studies have demonstrated that neuronally expressed acid-sensing ion channels (ASICs) are implicated in various neurological disorders including brain ischemia and seizures. Acidosis is a common feature of acute neurological conditions. It is postulated that a drop in pH may be the link between the pathological process and activation of NG2 cells. Such postulate immediately prompts the following questions: Do NG2 cells express ASICs? If so, what are their functional properties and subunit composition? Here, using a combination of electrophysiology, Ca2+ imaging and immunocytochemistry, we present evidence to demonstrate that NG2 cells of the rat hippocampus express high density of Ca2+-permeable ASIC1a channels compared with several types of hippocampal neurons. First, nucleated patch recordings from NG2 cells revealed high density of proton-activated currents. The magnitude of proton-activated current was pH dependent, with a pH for half-maximal activation of 6.3. Second, the current-voltage relationship showed a reversal close to the equilibrium potential for Na+. Third, psalmotoxin 1, a blocker specific for the ASIC1a channel, largely inhibited proton-activated currents. Fourth, Ca2+ imaging showed that activation of proton-activated channels led to an increase of [Ca2+]i. Finally, immunocytochemistry showed co-localization of ASIC1a and NG2 proteins in the hippocampus. Thus the acid chemosensor, the ASIC1a channel, may serve for inducing membrane depolarization and Ca2+ influx, thereby playing a crucial role in the NG2 cell response to injury following ischemia.