Targeting ribonuclease H (RNase H) has emerged as a highly promising strategy for treating HIV-1. In this study, a series of novel 3-hydrazonoindolin-2-one derivatives were designed and synthesized as potential inhibitors of HIV-1 RNase H. Notably, several of these derivatives displayed micromolar inhibitory activity. Among the compounds examined, the hit compound demonstrated potent inhibition of HIV-1 RNase H, boasting a Ki value of 2.31 μM. Additionally, the most potent compound of this general structure exhibited remarkable inhibitory activity, with Ki values of 0.55 μM. Through docking studies, the key interactions of this ligand within the active site of RNase H were uncovered. This novel chemical structure can be regarded as a prospective scaffold for the future development of RNase H inhibitors.

Ribonuclease H (RNase H) was identified as an important target for HIV therapy. Currently, no RNase H inhibitors have reached clinical status. Herein, a series of novel thiazolone[3,2-a]pyrimidine-containing RNase H inhibitors were developed, based on the hit compound 10i, identified from screening our in-house compound library. Some of these derivatives exhibited low micromolar inhibitory activity. Among them, compound 12b was identified as the most potent inhibitor of RNase H (IC50 = 2.98 μM). The experiment of magnesium ion coordination was performed to verify that this ligand could coordinate with magnesium ions, indicating its binding ability to the catalytic site of RNase H. Docking studies revealed the main interactions of this ligand with RNase H. A quantitative structure activity relationship (QSAR) was also conducted to disclose several predictive mathematic models. A molecular dynamics simulation was also conducted to determine the stability of the complex. Taken together, thiazolone[3,2-a]pyrimidine can be regarded as a potential scaffold for the further development of RNase H inhibitors.

Targeting Ribonuclease H (RNase H) has been considered a viable strategy for HIV therapy. In this study, a series of novel thiazolo[3, 2-a]pyrimidine derivatives were firstly designed and synthesized as potential inhibitors of HIV-1 RNase H. Among these compounds, A28 exhibited the most potent inhibition against HIV-1 RNase H with an IC50 value of 4.14 mu M, which was about 5-fold increase in potency than the hit compound A1 (IC50 = 21.49 mu M). To gain deeper insights into the structure-activity relationship (SAR), a CoMFA model was constructed to yield reasonable statistical results (q2 = 0.658 and R2 = 0.969). Results from magnesium ion chelation experiments and molecular docking studies revealed that these thiazolopyrimidine inhibitors may exert their inhibitory activity by binding to an allosteric site on RNase H at the interface between subunits p51 and p66. Furthermore, this analog demonstrated favorable physicochemical properties. Our findings provide valuable groundwork for further development of allosteric inhibitors targeting HIV-1 RNase H.

Our recent studies for nonnucleoside reverse transcriptase inhibitors identified a highly potent compound JK-4b against WT HIV-1 (EC50 = 1.0 nmol/L), but the poor metabolic stability in human liver microsomes (t(1/2 )= 14.6 min) and insufficient selectivity (SI = 2059) with high cytotoxicity (CC50 = 2.08 mmol/L) remained major issues associated with JK-4b. The present efforts were devoted to the introduction of fluorine into the biphenyl ring of JK-4b, leading to the discovery of a novel series of fluorine-substituted NH2-biphenyl-diarylpyrimidines with noticeable inhibitory activity toward WT HIV1 strain (EC50 = 1.8-349 nmol/L). The best compound 5t in this collection (EC50 = 1.8 nmol/L, CC50 = 117 mmol/L) was 32-fold in selectivity (SI = 66,443) compared to JK-4b and showed remarkable potency toward clinically multiple mutant strains, such as L100I, K103N, E138K, and Y181C. The metabolic stability of 5t was also significantly improved (t(1/2) = 74.52 min), approximately 5-fold higher than JK-4b in human liver microsomes (t(1/2 )= 14.6 min). Also, 5t possessed good stability in both human

Atrial fibrillation (AF) is the most common clinical sustained arrhythmia; clinical therapeutic drugs have low atrial selectivity and might cause more severe ventricle arrhythmias while stopping AF. As an anti-AF drug target with high selectivity on the atrial muscle cells, the undetermined crystal structure of Kv1.5 potassium channel impeded further new drug development. Herein, with the simulated 3D structure of Kv1.5 as the drug target, a series of 3-morpholine linked aromatic amino substituted 1H-indoles as novel Kv1.5 channel inhibitors were designed and synthesized based on target–ligand interaction analysis. The synthesis route was practical, starting from commercially available material, and the chemical structures of target compounds were characterized. It was indicated that compounds T16 and T5 (100 μM) exhibited favorable inhibitory activity against the Kv1.5 channel with an inhibition rate of 70.8 and 57.5% using a patch clamp technique. All compounds did not exhibit off-target effects against other drug targets, which denoted some selectivity on the Kv1.5 channel. Interestingly, twelve compounds exhibited favorable vasodilation activity on pre-contracted arterial rings in vitro using KCl or phenylephrine (PE) by a Myograph. The vasodilation rates of compounds T16 and T4 (100 μM) even reached over 90%, which would provide potential lead compounds for both anti-AF and anti-hypertension new drug development.

以邻氨基苯甲酰胺(5)为原料,依次经分子间环合、烷基化、氨解和分子内环合四步反应成功合成目标化合物3,4-二氢-2H-吡嗪并[2,1-b]喹唑啉-1,6-二酮(10),总收率为46.5％,其中,中间体(8)、(9)及目标化合物(10)均未见文献报道,其结构经1 H NMR和MS(ESI)确证,并采用MTT法初步评价目标化合物的体外抗肝癌活性.结果表明,3,4-二氢-2 H-吡嗪并[2,1-b]喹唑啉-1,6-二酮对SMMC-7721具有明显的抑制活性,优于阳性对照药舒尼替尼,可为进一步发现新型抗肝癌药物提供先导结构,也为该类衍生物的大量合成和结构改造提供参考方法.

The invention relates to the chemical synthesis of pharmaceutical API, and specifically to a method of synthesizing diclofenac sodium, which is a kind of nonsteroidal anti-inflammatory drug for relieving pain. The method includes: nitrating phenylacetate to prepare o-nitrophenylacetate (2); hydrogenating o-nitrophenylacetate (2) to prepare o-aminophenylacetate (3); amidating an amino group of o-aminophenylacetate (3) to obtain 2-(2-benzoylaminophenyl) acetate (4); 2-(2-benzoylaminophenyl) acetate (4) reacting with thionyl chloride to prepare a chloroimine intermediate, and then condensing the intermediate of chloroimine with 2,6-dichlorophenol using an inorganic base to prepare (E)-methyl-2-(2-((2,6-dichlorophenoxy)(phenyl)methyleneamino) phenyl ester (5); subjecting (E)-methyl-2-(2-((2,6-dichlorophenoxy)(phenyl)methyleneamino) phenyl ester (5) to Chapman rearrangement to afford methyl 2-(2-(N-(2,6-dichlorophenyl)benzoylamino)phenyl) ester (6); and hydrolyzing methyl 2-(2-(N-(2,6-dichlorophenyl)benzoylamino)phenyl) ester (6) to provide the target compound as of diclofenac sodium API. The overall yield is up to 67% based on methyl phenylacetate.

近年来有关硫脲衍生物的研究越来越多,通过查阅大量文献,发现许多硫脲类衍生物在早期临床研究中具有独特的抗菌抑制活性.总结了近年来有关N,N'-双取代硫脲类衍生物作为抗菌抑制剂的结构类型及研究进展.

总结了近年来有关N,N'-双取代硫脲类衍生物作为抗肿瘤抑制剂的结构类型及临床应用.发现了,许多硫脲类衍生物具有独特的抗肿瘤抑制活性.

近些年,有关吲唑类化合物的报道越来越多,吲唑及其氮氧化物的用途广泛,逐渐引起了药物化学界的广泛关注,其中不同的目标化合物具有不同药理活性.本文总结了近年来有关吲唑类化合物的结构类型及药理活性.

目的:通过曼尼希法和路易斯(Lewis)酸催化法合成芦竹碱,比较两种合成方法优劣.方法:通过正交试验考察反应物料比(吲哚:乙酸)、反应时间以及反应温度对曼尼希法合成芦竹碱的产率影响;考察反应溶剂、反应时间以及催化剂对Lewis酸催化法的影响.并研究不同底物对芦竹碱衍生物的合成影响.结果:曼尼希法合成芦竹碱,55℃时,n(吲哚):n(乙酸)=1:2反应12 h最佳,产率为88.5％.Lewis酸催化法的最佳条件是以乙醇为溶剂,ZnCl2为催化剂反应120 min,产率为93.1％.结论:Lewis酸催化法合成芦竹碱优于曼尼希法.Lewis酸催化法合成芦竹碱衍生物的结果表明,参与反应胺的位阻越大,产率越低;吲哚上引入供电子基可使产率提高,吸电子基的引入则会降低产率.

In order to improve the positional adaptability of our previously reported naphthyl diaryltriazines (NP-DATAs), synthesis of a series of novel biphenyl-substituted diaryltriazines (BP-DATAs) with a flexible side chain attached at the C-6 position is presented. These compounds exhibited excellent potency against wild-type (WT) HIV-1 with EC50 values ranging from 2.6 to 39 nmol/L and most of them showed low nanomolar anti-viral potency against a panel of HIV-1 mutant strains. Compounds 5j and 6k had the best activity against WT, single and double HIV-1 mutants and reverse transcriptase (RT) enzyme comparable to two reference drugs (EFV and ETR) and our lead compound NP-DATA (1). Molecular modeling disclosed that the side chain at the C-6 position of DATAs occupied the entrance channel of the HIV-1 reverse transcriptase non-nucleoside binding pocket (NNIBP) attributing to the improved activity. The preliminary structure-activity relationship and PK profiles were also discussed. (C) 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.

A novel series of dihydroquinazolin-2-amine derivatives were synthesized and evaluated for their anti-HIV-1 activity in MT-4 cell cultures. All of the molecules were active against wild-type HIV-1 with EC50 values ranging from 0.61 μM to 0.84 nM. The most potent inhibitor, compound 4b, had an EC50 value of 0.84 nM against HIV-1 strain IIIB, and thus was more active than the reference drugs efavirenz and etravirine. Moreover, most of the compounds maintained high activity (low-micromolar EC50 values) against strains bearing the reverse transcriptase (RT) E138K mutation. Compound 4b had EC50 values of 3.5 nM and 66 nM against non-nucleoside reverse transcriptase inhibitor-resistant strains bearing the RT E138K and RES056 mutations. In enzyme activity assays, compound 4b exhibited an IC50 value of 10 nM against HIV-1 RT. Preliminary SARs and molecular docking studies provide valuable insights for further optimization.

目的:初步探索研究磺胺类化合物与蛋白酪氨酸磷酸酶1B(PTP1B)的作用模式,建立具有良好预测能力的三维定量构效关系(3D-QSAR)模型.方法:通过分子对接(Surflex-Dock)研究阐明磺胺类化合物与PTP1B的结合模式,采用比较分子场分析(CoMFA)和比较分子相似性指数分析(CoMSIA)进行3D-QSAR研究.结果:分子对接结果显示,该类化合物可以与PTP1B酶的Site A位点很好地结合.建立的CoMFA模型交叉验证系数(q2)为0.516,CoMSIA模型q2为0.503.结论:该类化合物可与PTP1B酶很好地结合,建立的CoMFA模型和CoMSIA模型均具有良好的预测能力,为该类化合物的下一步设计提供理论依据.

The inductive effect related to foreign metal substitution has great effect on the redox behavior of transition metal oxides, which plays an important role in their electrochemical activities. In this work, we demonstrate the inductive effect in nickel oxide nanosheet arrays (NSAs) via doping with the lower electronegative element Mn, which has greatly improved their electrochemical capacitance and stability. Density functional theory (DFT) calculations show that the inductive effect in Mn-NiO increases the electron transport efficiency, enhances the adsorption energy of OH-, and also makes the compound more covalent. Therefore, Mn-NiO NSAs demonstrated a dramatically improved specific capacitance twofold better than that of pure NiO NSAs at a current density of 5 mA cm(-2) and higher stability without any decay of capacitance after 10 000 cycles at 30 mA cm(-2). Moreover, the hybrid supercapacitor device of Mn-NiO NSAs//graphene-CNT exhibited an excellent recycling stability after 50 000 cycles of charging/discharging at 6 A g(-1) with comparative energy density and power density.

A series of indazolyl-substituted piperidin-4-yl-aminopyrimidines (IPAPYs) were designed from two potent HIV-1 NNRTIs piperidin-4-yl-aminopyrimidine 3c and diaryl ether 4 as the lead compounds by molecular hybridization strategy. The target molecules 5a-q were synthesized and evaluated for their anti-HIV activities and cytotoxicities in MT-4 cells. 5a-q displayed moderate to excellent activities against wild-type (WT) HIV-1 with EC50 values ranging from 1.5 to 0.0064 μM. Among them, 5q was regarded as the most excellent compound against WT HIV-1 (EC50 = 6.4 nM, SI = 2500). And also, it displayed potent activities against K103 N (EC50 = 0.077 μM), Y181C (EC50 = 0.11 μM), E138K (EC50 = 0.057 μM), and moderate activity against double mutants RES056 (EC50 = 8.7 μM). Moreover, the structure-activity relationships (SARs) were summarized, and the molecular docking was performed to investigate the binding mode of IPAPYs and HIV-1 reverse transcriptase.

Disclosed is a method of synthesizing a series of compounds with the structure of (1S, 5R)-lactone. In the method, under the catalysis of a chiral phosphonic acid, substituted bicyclo[3.2.0]-hept-2-en-6-one (II) as a substrate is reacted with hydrogen peroxide for enantioselective Baeyer-Villiger oxidation to produce a chiral lactone (I). This method involves mild reaction conditions, simple operation, quantitatively recyclable catalyst and high reaction selectivity and stereoselectivity, which is suitable for industrial production.

Given their ability to reduce activated alkenes thereby generating up to two stereogenic centers, ene reductases from the old yellow enzyme (OYE) family have received much attention as effective biocatalysts. Through genome mining, a "classical" OYE, KYE2, was identified from Kluyveromyces marxianus CBS4857 and fully characterized in vitro. This NADPH-dependent enzyme displayed a broad substrate spectrum for the bioreduction of activated alkenes. The highly stereoselective synthesis (>95% ee) of various (R)-profen methyl esters, including the synthesis of (R)-flurbiprofen methyl ester on a semi-preparative scale further demonstrates the potential of KYE2 to be developed as a general biocatalyst for chemical synthesis.

Chiral syn-1,3-diols are fundamental structural motifs in many natural products and drugs. The traditional Narasaka-Prasad diastereoselective reduction from chiral β-hydroxyketones is an important process for the synthesis of these functionalized syn-1,3-diols, but it is of limited applicability for large-scale synthesis because (1) highly diastereoselective control requires extra explosive and flammable Et2BOMe as a chelating agent under cryogenic conditions and (2) only a few functional syn-1,3-diol scaffolds are available. Those involving halogen-functionalized syn-1,3-diols are much less common. There are no reported diastereoselective reactions involving chemical fixation of CO2/bromocyclization of homoallylic alcohols to halogen-containing chiral syn-1,3-diols. Herein, we report an asymmetric synthesis of syn-1,3-diol derivatives via direct diastereoselective carboxylation/bromocyclization with both relative and absolute stereocontrol utilizing chiral homoallylic alcohols and CO2 in one pot with up to 91% yield, > 99% ee, and >19:1 dr. The power of this methodology has been demonstrated by the asymmetric synthesis of statins at the pilot plant scale.