AMPA受体拮抗剂NS1209的合成

以5-溴异喹啉为起始原料,经过9步反应合成了AMPA受体拮抗剂——NS1209,总产率37.3％,其结构经1H NMR和MS确证.     

非核苷类HCV NS5B聚合酶抑制剂

全球约有1.7亿人感染丙型肝炎病毒(HCV),至今尚无有效的疫苗和治疗药物。目前干扰素-α和利巴韦林联用抗HCV 的标准治疗方案存在严重不良反应。近年来,新型抗HCV的研究主要集中于针对病毒感染的特异性靶点寻找新的抑制剂。NS5B聚合酶因其在HCV RNA基因组复制中的关键性作用,是目前抗HCV药物设计的重要靶点之一。NS5B聚合酶抑制剂可分为核苷类抑制剂(NIs)和非核苷类抑制剂(NNIs)。自从第一个NS5B NNIs苯并咪唑类化合物被报道以来,大量不同结合位点NS5B NNIs相继被报道,一些化合物在临床研究中表现出了可喜的疗效。本文综述了苯并噻二嗪类、苯并咪唑类、吲哚类、噻吩羧酸类、喹啉酮类、二氢吡喃类和二酮酸类等 NS5B NNIs的研究进展,旨在为该类抑制剂的开发研究提供参考。     

Copper complexes of two isomeric NS2-macrocycles

Two isomeric NS₂-macrocycles incorporating a xylyl group at ortho (o -L) and meta (m -L) positions were employed and their copper complexes (1?C5) were prepared and structurally characterized. The copper(II) nitrate complexes [Cu(L)(NO₃)₂] (1: L = o -L, 2: L = m -L) for both ligands were isolated. In each case, the copper center is five-coordinated with a distorted square pyramidal geometry. Despite the overall geometrical similarity, 1 and 2 show the different ligand conformation due to the discriminated packing pattern. Reaction of o -L with copper(II) perchlorate afforded complex 3 containing two independent complex cations [Cu(o -L)(H₂O)(DMF)(ClO₄)]⁺ and [Cu(o -L)(H₂O)(DMF)]²⁺; the coordination geometry of the former is a distorted octahedron while the latter shows a distorted square pyramidal arrangement. In the reactions of copper(I) halides (I or Br), o -L gave a mononuclear complex [Cu(o-L)I] (4) with a distorted tetrahedral geometry, while m -L afforded a unique exodentate 2:1 (ligand-to-metal) complex [trans-Br₂Cu(m-L)₂] (5) adopting a trans-type square-planar arrangement.     

A Computational Approach Applied to the Study of Potential Allosteric Inhibitors Protease NS2B/NS3 from Dengue Virus

Dengue virus (DENV) is a danger to more than 400 million people in the world, and there is no specific treatment. Thus, there is an urgent need to develop an effective method to combat this pathology. NS2B/NS3 protease is an important biological target due it being necessary for viral replication and the fact that it promotes the spread of the infection. Thus, this study aimed to design DENV NS2B/NS3pro allosteric inhibitors from a matrix compound. The search was conducted using the Swiss Similarity tool. The compounds were subjected to molecular docking calculations, molecular dynamics simulations (MD) and free energy calculations. The molecular docking results showed that two compounds, ZINC000001680989 and ZINC000001679427, were promising and performed important hydrogen interactions with the Asn152, Leu149 and Ala164 residues, showing the same interactions obtained in the literature. In the MD, the results indicated that five residues, Lys74, Leu76, Asn152, Leu149 and Ala166, contribute to the stability of the ligand at the allosteric site for all of the simulated systems. Hydrophobic, electrostatic and van der Waals interactions had significant effects on binding affinity. Physicochemical properties, lipophilicity, water solubility, pharmacokinetics, druglikeness and medicinal chemistry were evaluated for four compounds that were more promising, showed negative indices for the potential penetration of the Blood Brain Barrier and expressed high human intestinal absorption, indicating a low risk of central nervous system depression or drowsiness as the the side effects. The compound ZINC000006694490 exhibited an alert with a plausible level of toxicity for the purine base chemical moiety, indicating hepatotoxicity and chromosome damage in vivo in mouse, rat and human organisms. All of the compounds selected in this study showed a synthetic accessibility (SA) score lower than 4, suggesting the ease of new syntheses. The results corroborate with other studies in the literature, and the computational approach used here can contribute to the discovery of new and potent anti-dengue agents.     

Reaction of NS with N3

Thionitrosyl hexafluoroarsenate, [NS][AsF₆], reacted with caesium azide, [Cs][N₃], to form S₂N₂ which polymerized to give (SN)_x. The structures of the following likely intermediate species were calculated at correlated MP2/6–31G(d,p) level of theory (relative energies in kcal mol⁻¹): thionitrosyl azide, N₃---N=S (37.8), thiazyl azide, N₃---SN (39.2) and cyclic N₄S (0.0).^‡     

Potassium bromide catalyzed NS bond formation via oxidative dehydrogenation

N-Substituted benzo[d]isothiazol-3(2H)-ones are a family of compounds with extremely important application. Recently, we have developed a new green pathway to synthesize these compounds via potassium bromide-catalyzed intramolecular oxidative dehydrogenative cyclization. This reaction has high functional group tolerance and affords excellent yield even in gram scale.     

Insight into the structural requirements of narlaprevir-type inhibitors of NS3/NS4A protease based on HQSAR and molecular field analyses

In the life cycle of hepatitis C virus (HCV), NS3/NS4A protease has been proved to play a vital role in the replication of the HCV virus. Narlaprevir and its derivatives, the inhibitors of NS3/NS4A, would be potentially developed as important anti-HCV drugs in the future. In this study, quantitative structure-activity relationship (QSAR) analyses for 190 narlaprevir derivatives were conducted using comparative molecular field analysis (CoMFA), comparative molecular indices analysis (CoMSIA) and hologram quantitative structure-activity relationship (HQSAR) techniques. Both of the best CoMFA and HQSAR models showed statistical significance for the training set and good predictive accuracy for the test set, which strongly manifested the robustness of the CoMFA and HQSAR models. The CoMFA contour maps and the HQSAR contribution maps were both presented. Furthermore, based on the essential factors for ligand binding derived from the QSAR models, sixteen new derivatives were designed and some of them showed higher inhibitory activities confirmed by our models and molecular docking studies. General speaking, this study provides useful suggestions for the design of potential anti-HCV drugs.     

A pi-stacked 1,2,3-dithiazolyl radical. Preparation and solid state characterization of (Cl2C3NS)(ClC2NS2)

Crystals of (Cl2C3NS)(ClC2NS2), an isothiazolyl-substituted 1,2,3-dithiazolyl radical, consist of evenly spaced, slipped pi-stacks; magnetic and conductivity measurements indicate the material is a Mott insulator with sigma RT = 2 x 10(-7) S cm-1.     

Discovery of Bispecific Lead Compounds from Azadirachta indica against ZIKA NS2B-NS3 Protease and NS5 RNA Dependent RNA Polymerase Using Molecular Simulations

Zika virus (ZIKV) has been characterized as one of many potential pathogens and placed under future epidemic outbreaks by the WHO. However, a lack of potential therapeutics can result in an uncontrolled pandemic as with other human pandemic viruses. Therefore, prioritized effective therapeutics development has been recommended against ZIKV. In this context, the present study adopted a strategy to explore the lead compounds from Azadirachta indica against ZIKV via concurrent inhibition of the NS2B-NS3 protease (ZIKV^pro) and NS5 RNA dependent RNA polymerase (ZIKV^RdRp) proteins using molecular simulations. Initially, structure-based virtual screening of 44 bioflavonoids reported in Azadirachta indica against the crystal structures of targeted ZIKV proteins resulted in the identification of the top four common bioflavonoids, viz. Rutin, Nicotiflorin, Isoquercitrin, and Hyperoside. These compounds showed substantial docking energy (−7.9 to −11.01 kcal/mol) and intermolecular interactions with essential residues of ZIKV^pro (B:His⁵¹, B:Asp⁷⁵, and B:Ser¹³⁵) and ZIKV^RdRp (Asp⁵⁴⁰, Ile⁷⁹⁹, and Asp⁶⁶⁵) by comparison to the reference compounds, O7N inhibitor (ZIKV^pro) and Sofosbuvir inhibitor (ZIKV^RdRp). Besides, long interval molecular dynamics simulation (500 ns) on the selected docked poses reveals stability of the respective docked poses contributed by intermolecular hydrogen bonds and hydrophobic interactions. The predicted complex stability was further supported by calculated end-point binding free energy using molecular mechanics generalized born surface area (MM/GBSA) method. Consequently, the identified common bioflavonoids are recommended as promising therapeutic inhibitors of ZIKV^pro and ZIKV^RdRp against ZIKV for further experimental assessment.     

Hepatitis C virus NS3 protease requires its NS4A cofactor peptide for optimal binding of a boronic acid inhibitor as shown by NMR

NMR spectroscopy was used to characterize the hepatitis C virus (HCV) NS3 protease in a complex with the 24 residue peptide cofactor from NS4A and a boronic acid inhibitor, Ac-Asp-Glu-Val-Val-Pro-boroAlg-OH. Secondary-structure information, NOE constraints between protease and cofactor, and hydrogen-deuterium exchange rates revealed that the cofactor was an integral strand in the N-terminal beta-sheet of the complex as observed in X-ray crystal structures. Based upon chemical-shift perturbations, inhibitor-protein NOEs, and the protonation state of the catalytic histidine, the boronic acid inhibitor was bound in the substrate binding site as a transition state mimic. In the absence of cofactor, the inhibitor had a lower affinity for the protease. Although the inhibitor binds in the same location, differences were observed at the catalytic site of the protease.