Syntheses,Cholinesterases Inhibition,and Molecular Docking Studies of Pyrido[2,3‐b]pyrazine Derivatives

Cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), have a role in cholinergic deficit which evidently leads to Alzheimer's disease (AD). Inhibition of cholinesterases with small molecules is an attractive strategy in AD therapy. This study demonstrates synthesis of pyrido[2,3‐b]pyrazines ( 6a ‐ 6q ) series, their inhibitory activities against both cholinesterases, AChE and BChE, and molecular docking studies. The bioactivities data of pyrido[2,3‐b]pyrazines showed 3‐(3′‐nitrophenyl)pyrido[2,3‐b]pyrazine 6n a potent dual inhibitor among the series against both AChE and BChE with IC₅₀ values of 0.466 ± 0.121 and 1.89 ± 0.05 μm , respectively. The analogues 3‐(3′‐methylphenyl)pyrido[2,3‐b]pyrazine 6c and 3‐(3′‐fluorophenyl)pyrido[2,3‐b]pyrazine 6f were found to be selective inhibition for BChE with IC₅₀ values of 0.583 ± 0.052 μm and AChE with IC₅₀ value of 0.899 ± 0.10 μm , respectively. Molecular docking studies of the active compounds suggested the putative binding modes with cholinesterases. The potent compounds among the series could potentially serves as good leads for the development of new cholinesterase inhibitors.     

Effects of polyunsaturated fatty acids on voltage-gated K+ and Na+ channels in rat olfactory receptor neurons

Although the polyunsaturated fatty acids arachidonic acid (AA) and docosahexaenoic acid (DHA) are enriched in the olfactory mucosa, their possible contribution to olfactory transduction has not been investigated. This study characterized their effects on voltage‐gated K⁺ and Na⁺ channels of rat olfactory receptor neurons. Physiological (3–10 µm ) concentrations of AA and DHA potently and irreversibly inhibited the voltage‐gated K⁺ current in a voltage‐independent manner. In addition, both compounds significantly reduced the inhibitory potency of the odorants acetophenone and amyl acetate at these channels. By comparison, the steady‐state effects of both AA and DHA on the voltage‐gated Na⁺ channel were relatively weak, with half‐maximal inhibition requiring ≈ 35 µm of either compound. However, a surprising finding was that the initial application of 3 µm AA to a naïve neuron caused a strong but transient inhibition of the Na⁺ current. The channels became almost completely resistant to this inhibition within 1 min, and a 2‐min wash in control solution was insufficient to restore the strong inhibitory effect. These observations suggest that polyunsaturated fatty acids have the potential to strongly influence the coding of odorant information by olfactory receptor neurons.     

Select Acetophenones Modulate Flagellar Motility in Chlamydomonas

Acetophenones were screened for activity against positive phototaxis of Chlamydomonas cells, a process that requires co-ordinated flagellar motility. The structure–activity relationships of a series of acetophenones are reported, including acetophenones that affect flagellar motility and cell viability. Notably, 4-methoxyacetophenone, 3,4-dimethoxyacetophenone, and 4-hydroxyacetophenone induced negative phototaxis in Chlamydomonas, suggesting interference with activity of flagellar proteins and control of flagellar dominance.     

手性氨基醇用于苯乙酮的不对称还原研究

合成了（１Ｒ，２Ｓ）－１－二丁基氨基－１，２－二氢－２－茚醇及其对映体，首次将此类手性氨基醇用于苯乙酮的不对称还原反应研究，用温和的还原剂ＫＢＨ４，得到的还原产物１－苯基乙醇其最佳对映体过量值达８１％．同时还调查了反应时间对转化率和对映体过量值的影响，确定７０ｈ为最合适的反应时间。     

In vitro inhibitory effects of some acetophenone derivatives on some metabolic enzymes and molecular docking

In this study, the acetophenone derivatives 1 – 6 were found to be effective inhibitor molecules for α-glycosidase, human carbonic anhydrases I and II (hCA I/II), and acetylcholinesterase (AChE), with K_i values in the range of 167.98 ± 25.06 to 304.36 ± 65.45 µM for α-glycosidase, 555.76 ± 56.07 to 1,043.66 ± 98.78 µM for hCA I, 598.63 ± 90.04 to 945.76 ± 74.50 µM for hCA II, and 71.34 ± 11.25 to 143.75 ± 31.27 µM for AChE, and IC₅₀ values of 73.65–101.13 µM for tyrosinase. In the last step, molecular docking calculations were performed to compare the biological activities of molecules with their docking scores in these enzymes. The interactions of the studied molecules against human α-galactosidase (PDB ID: 1R47), hCA I (PDB ID: 3LXE), human AChE (PDB ID: 4M0E), hCA II (PDB ID: 5AML), and human tyrosinase (PDB ID: 5M8Q) were examined to compare the biological activity values. The ADME/T analysis (adsorption, distribution, metabolism, and discharge) was then performed for the future use of these molecules as drugs.     

The Anomalous Hydrolytic Behavior of 1-Phenylvinyl Phosphate

The kinetics of hydrolysis of 1-phenylvinyl phosphate, 1, were studied over a pH range of 1 to 8.3 and over a pD range of 1 to 5.6 at 25°C and µ = 0.5 M with sodium chloride. The hydrolytic behavior of 1 was found to differ, in many respects, from that of alkyl and aryl phosphomonoesters. First, the rates of hydrolysis of 1 were extremely rapid and, in the hydronium ion-catalyzed region, gave a solvent deuterium isotope effect (k _H/k _D) of 3.20. Also, the ¹H-NMR spectrum of acetophenone formed upon complete hydrolysis of 1 in D₂O (pD 1.2) revealed that only one deuterium atom was incorporated into the methyl group. Hence, the evidence was consistent with a rate-limiting and nonreversible proton transfer from the solvent to 1. In addition, using an H₂ ¹⁸O labeling study in conjunction with ³¹P-NMR analysis, the hydrolytic mechanism appeared to involve nucleophilic attack by water at both the -carbon and the phosphorus atom with concurrent C–O and P–O bond fission. Second, in the pH region where the monoanionic species of 1 predominated, buffers had a pronounced catalytic effect on the hydrolysis rate; there appeared to be a normal solvent deuterium isotope effect; and the rate constant, k_o, showed a positive deviation from the established Brønsted relationship. The dissimilarities between 1 and alkyl and aryl phosphomonoesters supported the involvement of an alternate dephosphorylation pathway. One potential mechanism for the hydrolysis of 1, consistent with the experimental findings, might be rate-limiting and nonreversible protonation of the -carbon of the olefmic bond, resulting in the formation of a rapidly hydrated carbonium ion intermediate, a mechanism similar to that proposed for the more acidic pH region. Alternatively, a concerted mechanism involving proton transfer with expulsion of a monomeric metaphos-phate anion might be operating.     

手性还原剂用于苯乙酮的不对称还原研究

（１Ｓ，２Ｒ）－１－二丁氨基－１，２－二氢－２－茚醇（ＲＯＨ）与氢化铝锂形成的手性试剂首次用于苯乙酮的不对称还原研究．根据手性试剂制备后的使用方法（方法Ａ∶立即使用；方法Ｂ∶回流１０ ｍ ｉｎ 后使用），苯乙酮还原后可分别给出对映体过量值达６０％ ～７６％ 的不同主产物Ｒ－（＋ ）－１－苯基乙醇和Ｓ－（－）－１－苯基乙醇．研究了反应物物质的量之比（ＬｉＡｌＨ４ ｖＲＯＨｖＰｈＣＯＭｅ）对立体选择性的影响，当反应物物质的量之比为１．０ｖ１．５０ｖ１．５０时有较高的对映体过量值和转化率．这种手性还原剂为不对称合成光学活性醇提供了一种选择．     

Hypolipidemic Activity of o-(N-Phthalimido)acetophenone in Sprague Dawley Rats

o-(N-Phthalimido)acetophenone has proven to be an effective hypolipidemic agent in rats at 20 mg/kg/ day orally. The agent suppressed the activity of the rate-limiting enzyme of the liver involved in de novo synthesis of triglycerides. The synthetic rate-limiting enzyme for cholesterol esters was also inhibited by the drug in vivo. o-(N-Phthalimido)acetophenone lowered cholesterol in the liver and the aorta wall and generally caused an increase in phospholipids in body tissues. Serum lipoproteins were modulated by the drug with a decrease in cholesterol and triglycerides in the chylomicron, very low-density lipoproteins (VLDL), and low-density lipoproteins (LDL) and an increase in high-density lipoprotein (HDL) cholesterol. The phospholipid content was increased in the chylomicron, VLDL, and LDL fractions. In hyperlipidemic rats, o-(N-phthalimido)acetophenone lowered elevated blood lipid levels at 20 mg/kg/day orally after 3 weeks of administration. The hypolipidemic rat after drug treatment had a lower LDL cholesterol and a higher HDL cholesterol content, which is therapeutically desirable to protect against cardiovascular disease.     

黄芩炒炭前后挥发性成分的GC-MS分析

目的:比较黄芩炒炭前后挥发性成分的含量变化,为阐明其炮制机制提供参考。方法:利用水蒸气蒸馏法提取黄芩中挥发油,利用GC-MS分析黄芩炮制品中挥发油成分的组成及含量变化,DB-5MS气相色谱柱(0.25 mm×30 m,0.25μm),载气为氦气,电子轰击电离源,离子源温度280℃,质谱接口温度280℃,电子能量70 e V。全离子扫描,质量扫描范围m/z 33~350,流速40 m L·min~(-1),分流比5∶1,采集延时2 min,图谱采集时间50.0 min。通过检索比对NIST-05标准质谱图谱库,鉴定样品挥发油中化学成分。结果:生黄芩、黄芩炭中挥发油提取量分别为1.3,0.8μL·g~(-1),GC-MS共鉴定了50种挥发油成分,其中生黄芩25种,黄芩炭31种。根据峰面积归一化法分析,鉴定的成分分别占生黄芩、黄芩炭饮片挥发油总量的100.00%,99.93%。结论:黄芩炒炭后挥发性成分含量有所降低,挥发性成分组成有所改变,但炒炭后挥发性成分尚存,可为阐释黄芩"炒炭存性"的炮制机制提供科学依据。