共查询到20条相似文献,搜索用时 15 毫秒
1.
E Feng D Ye J Li D Zhang J Wang F Zhao R Hilgenfeld M Zheng H Jiang H Liu 《ChemMedChem》2012,7(9):1527-1536
The recent emergence of the highly pathogenic H5N1 subtype of avian influenza virus (AIV) and of the new type of human influenza A (H1N1) have emphasized the need for the development of effective anti‐influenza drugs. Presently, neuraminidase (NA) inhibitors are widely used in the treatment and prophylaxis of human influenza virus infection, and tremendous efforts have been made to develop more potent NA inhibitors to combat resistance and new influenza viruses. In this review, we discuss the structural characteristics of NA catalytic domains and the recent developments of new NA inhibitors using structure‐based drug design strategies. These drugs include analogues of zanamivir, analogues of oseltamivir, analogues of peramivir, and analogues of aromatic carboxylic acid and present promising options for therapeutics or leads for further development of NA inhibitors that may be useful in the event of a future influenza pandemic. 相似文献
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Ádám Hadházi Linghui Li Dr. Benjamin Bailly Dr. Andrea Maggioni Gael Martin Dr. Larissa Dirr Jeffrey C. Dyason Dr. Robin J. Thomson Prof. George F. Gao Prof. Anikó Borbás Dr. Thomas Ve Dr. Mauro Pascolutti Prof. Mark von Itzstein 《ChemMedChem》2018,13(8):785-789
Influenza virus infection continues to cause significant, often severe, respiratory illness worldwide. A validated target for the development of anti‐influenza agents is the virus surface protein sialidase. In the current study, we have discovered a highly potent inhibitor of influenza virus sialidase, based on a novel sialosyl sulfonate template. The synthesised 3‐guanidino sialosyl α‐sulfonate, a sulfonozanamivir analogue, inhibits viral replication in vitro at the nanomolar level, comparable to that of the anti‐influenza drug zanamivir. Using protein X‐ray crystallography we show that the sialosyl α‐sulfonate template binds within the sialidase active site in a 1C4 chair conformation. The C1‐sulfonate moiety forms crucial and strong‐binding interactions with the active site's triarginyl cluster, while the 3‐guanidino moiety interacts significantly with conserved active site residues. This sulfonozanamivir analogue provides a new direction in anti‐influenza virus drug development. 相似文献
4.
Dr. Paola Rota Dr. Paolo La Rocca Dr. Marco Piccoli Dr. Marco Montefiori Dr. Federica Cirillo Prof. Lars Olsen Prof. Marica Orioli Prof. Pietro Allevi Prof. Luigi Anastasia 《ChemMedChem》2018,13(3):236-240
Neuraminidase activity is essential for the infection and propagation of paramyxoviruses, including human parainfluenza viruses (hPIVs) and the Newcastle disease virus (NDV). Thus, many inhibitors have been developed based on the 2‐deoxy‐2,3‐didehydro‐d ‐N‐acetylneuraminic acid inhibitor (DANA) backbone. Along this line, herein we report a series of neuraminidase inhibitors, having C4 (p‐toluenesulfonamido and azido substituents) and C5 (N‐perfluorinated chains) modifications to the DANA backbone, resulting in compounds with 5‐ to 15‐fold greater potency than the currently most active compound, the N‐trifluoroacetyl derivative of DANA (FANA), toward the NDV hemagglutinin‐neuraminidase (NDV‐HN). Remarkably, these inhibitors were found to be essentially inactive against the human sialidase NEU3, which is present on the outer layer of the cell membrane and is highly affected by the current NDV inhibitor FANA. 相似文献
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Dr. Shuwen Wu Jing Huang Dr. Sabrina Gazzarrini Si He Lihua Chen Dr. Jun Li Dr. Li Xing Dr. Chufang Li Prof. Ling Chen Dr. Constantinos G. Neochoritis George P. Liao Prof. Haibing Zhou Prof. Alexander Dömling Prof. Anna Moroni Prof. Wei Wang 《ChemMedChem》2015,10(11):1837-1845
Basic bulky amines such as amantadine are well‐characterized M2 channel blockers, useful for treating influenza. Herein we report our surprising findings that charge‐neutral, bulky isocyanides exhibit activities similar to—or even higher than—that of amantadine. We also demonstrate that these isocyanides have potent growth inhibitory activity against the H5N1 virus. The ?NH2 to ?N≡C group replacement within current anti‐influenza drugs was found to give compounds with high activities at low‐micromolar concentrations. For example, a tenfold improvement in potency was observed for 1‐isocyanoadamantane ( 27 ), with an EC50 value of 0.487 μm against amantadine‐sensitive H5N1 virus as determined by both MTT and plaque‐reduction assays, without showing cytotoxicity. Furthermore, the isocyanide analogues synthesized in this study did not inhibit the V27A or S31N mutant M2 ion channels, according to electrophysiology experiments, and did not exhibit activity against amantadine‐resistant virus strains. 相似文献
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Lukas Werner Ales Machara Tomas Hudlicky 《Advanced Synthesis \u0026amp; Catalysis》2010,352(1):195-200
A short chemoenzymatic and azide‐free synthesis of oseltamivir was attained with the key steps consisting of a one‐pot Dauben–Michno oxidative transposition and amination and a reductive transposition of an acrylate. 相似文献
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In recent years, clinical symptoms resulting from West Nile virus (WNV) infection have worsened in severity, with an increased frequency in neuroinvasive diseases among the elderly. As there are presently no successful therapies against WNV for use in humans, continual efforts to develop new chemotherapeutics against this virus are highly desired. The viral NS2B‐NS3 protease is a promising target for viral inhibition due to its importance in viral replication and its unique substrate preference. In this study, a WNV NS2B‐NS3 protease inhibitor with a 2‐{6‐[2‐(5‐phenyl‐4H‐[1,2,4]triazol‐3‐ylsulfanyl)acetylamino]benzothiazol‐2‐ylsulfanyl}acetamide scaffold was identified during screening. Optimization of this initial hit by synthesis and screening of a focused compound library with this scaffold led to the identification of a novel uncompetitive inhibitor ( 1 a24 , IC50=3.4±0.2 μM ) of the WNV NS2B‐NS3 protease. Molecular docking of 1 a24 into the WNV protease showed that the compound interferes with productive interactions of the NS2B cofactor with the NS3 protease and is an allosteric inhibitor of the WNV NS3 protease. 相似文献
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Martin Hintersteiner Dr. Thierry Kimmerlin Dr. Geraldine Garavel Dr. Thorsten Schindler Dr. Roman Bauer Dr. Nicole‐Claudia Meisner Dr. Jan‐Marcus Seifert Dr. Volker Uhl Dr. Manfred Auer Prof. Dr. 《Chembiochem : a European journal of chemical biology》2009,10(6):994-998
New and improved : The incorporation of a 6‐chlorotryptophan (6‐Cl‐Trp) into a β‐peptide (M)‐314 helix leads to a high‐affinity hDM2 inhibitor, as demonstrated by fluorescence fluctuation analysis at single molecule resolution. When conjugated to penetratin, the newly derived hDM2 binder specifically inhibits tumour cell growth in vitro.
9.
Jiang Weng Jun‐Ming Li Feng‐Quan Li Zhi‐Sheng Xie Gui Lu 《Advanced Synthesis \u0026amp; Catalysis》2012,354(10):1961-1970
An asymmetric domino nitro‐Michael/Horner–Wadsworth–Emmons (HWE) reaction involving α,β‐unsaturated aldehydes and nitro phosphonates has been developed, which gave 4,5‐disubstituted cyclohexenecarboxylates with high stereoselectivities (dr up to >20:1, ee 83–92%) in good yields (44–76%). Furthermore, using this methodology as a key step, a short and practical synthesis of pharmaceutically useful compounds (such as the dipeptidyl peptidase IV inhibitor ABT‐341 and an influenza neuraminidase inhibitor) has also been accomplished. 相似文献
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Mohan Kasula Tuniki Balaraju Dr. Massaki Toyama Anandarajan Thiyagarajan Dr. Chandralata Bal Dr. Masanori Baba Dr. Ashoke Sharon 《ChemMedChem》2013,8(10):1673-1680
Computer‐aided approaches coupled with medicinal chemistry were used to explore novel carbocyclic nucleosides as potential anti‐hepatitis C virus (HCV) agents. Conformational analyses were carried out on 6‐amino‐1H‐pyrazolo[3,4‐d]pyrimidine (6‐APP)‐based carbocyclic nucleoside analogues, which were considered as nucleoside mimetics to act as HCV RNA‐dependent RNA polymerase (RdRp) inhibitors. Structural insight gained from the modeling studies revealed the molecular basis behind these nucleoside mimetics. The rationally chosen 6‐APP analogues were prepared and evaluated for anti‐HCV activity. RdRp SiteMap analysis revealed the presence of a hydrophobic cavity near C7 of the nucleosides; introduction of bulkier substituents at this position enhanced their activity. Herein we report the identification of an iodinated compound with an EC50 value of 6.6 μM as a preliminary anti‐HCV lead. 相似文献
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Infectious diseases continue to be one of the major contributors to human morbidity. The rapid rate at which pathogenic microorganisms have developed resistance against frontline antimicrobials has compelled scientists to look for new alternatives. Given their vast antimicrobial repertoire, substantial research effort has been dedicated toward the development of antimicrobial peptides (AMPs) as alternative drugs. However, inherent limitations of AMPs have driven substantial efforts worldwide to develop synthetic mimics of AMPs. This review focuses on the progress that has been made toward the development of small molecules that emulate the properties of AMPs, both in terms of design and biological activity. Herein we provide an extensive discussion of the structural features of various designs and we examine biological properties that have been exploited. Furthermore, we raise a number of questions for which the field has yet to provide solutions and discuss possible future research directions that remain either unexploited or underexploited. 相似文献
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Dr. Chie Hashimoto Dr. Wataru Nomura Dr. Tetsuo Narumi Dr. Masayuki Fujino Dr. Hiroshi Tsutsumi Masaki Haseyama Prof. Naoki Yamamoto Dr. Tsutomu Murakami Prof. Hirokazu Tamamura 《ChemMedChem》2013,8(10):1668-1672
The human immunodeficiency virus type 1 (HIV‐1) uses CD4 and the co‐receptor CCR5 or CXCR4 in the process of cell entry. The negatively charged extracellular domains of CXCR4 (CXCR4‐ED) interact with positive charges on the V3 loop of gp120, facilitating binding via electrostatic interactions. The presence of highly conserved positively charged residues in the V3 loop suggests that CXCR4‐ED‐derived inhibitors might be broadly effective inhibitors. Synthetic peptide derivatives were evaluated for anti‐HIV‐1 activity. The 39‐mer extracellular N‐terminal region (NT) was divided into three fragments with 10‐mer overlapping sites ( N1 – N3 ), and these linear peptides were synthesized. Peptide N1 contains Met 1–Asp 20 and shows significant anti‐HIV‐1 activity. Extracellular loops 1 and 2 (ECL1 and 2) were mimicked by cyclic peptides C1 and C2 , which were synthesized by chemoselective cyclization. Cyclic peptides C1 and C2 show higher anti‐HIV‐1 activity than their linear peptide counterparts, L1 and L2 . The cytotoxicities of C1 and C2 are lower than those of L1 and L2 . These results indicate that Met 1–Asp 20 segments of the NT and cyclic peptides of ECL1 and ECL2 are potent anti‐HIV‐1 drug candidates. 相似文献
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Dr. Kantharaju Kamanna Dr. Rachna Aneja Caitlin Duffy Pamela Kubinski Dr. Diogo Rodrigo Moreira Lauren D. Bailey Dr. Karyn McFadden Dr. Arne Schön Andrew Holmes Dr. Ferit Tuzer Dr. Mark Contarino Prof. Ernesto Freire Prof. Irwin M. Chaiken 《ChemMedChem》2013,8(2):322-328
We investigated the derivation of non‐natural peptide triazole dual receptor site antagonists of HIV‐1 Env gp120 to establish a pathway for developing peptidomimetic antiviral agents. Previously we found that the peptide triazole HNG‐156 [R‐I‐N‐N‐I‐X‐W‐S‐E‐A‐M‐M‐CONH2, in which X=ferrocenyltriazole‐Pro (FtP)] has nanomolar binding affinity to gp120, inhibits gp120 binding to CD4 and the co‐receptor surrogate mAb 17b, and has potent antiviral activity in cell infection assays. Furthermore, truncated variants of HNG‐156, typified by UM‐24 (Cit‐N‐N‐I‐X‐W‐S‐CONH2) and containing the critical central stereospecific LX‐LW cluster, retain the functional characteristics of the parent peptide triazole. In the current work, we examined the possibility of replacing natural with unnatural residue components in UM‐24 to the greatest extent possible. The analogue with the critical “hot spot” residue Trp 6 replaced with L ‐3‐benzothienylalanine (Bta) (KR‐41), as well as a completely non‐natural analogue containing D ‐amino acid substitutions outside the central cluster (KR‐42, DCit‐DN‐DN‐DI‐X‐Bta‐DS‐CONH2), retained the dual receptor site antagonism/antiviral activity signature. The results define differential functional roles of subdomains within the peptide triazole and provide a structural basis for the design of metabolically stable peptidomimetic inhibitors of HIV‐1 Env gp120. 相似文献
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Dr. Luca Sancineto Dr. Nunzio Iraci Dr. Serena Massari Dr. Vanessa Attanasio Dr. Gianmarco Corazza Dr. Maria Letizia Barreca Dr. Stefano Sabatini Dr. Giuseppe Manfroni Dr. Nilla Roberta Avanzi Prof. Violetta Cecchetti Prof. Christophe Pannecouque Prof. Alessandro Marcello Dr. Oriana Tabarrini 《ChemMedChem》2013,8(12):1941-1953
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Ping Xu Jian Hua Qiu Yi Nan Zhang Jing Chen Peng George Wang Bing Yan Jing Song Ri Mo Xi Zi Xin Deng Cui Qing Ma 《Advanced Synthesis \u0026amp; Catalysis》2007,349(10):1614-1618
N‐Acetyl‐D ‐neuraminic acid (Neu5Ac) was efficiently synthesized from lactate and a mixture of N‐acetyl‐D ‐glucosamine (GlcNAc) and N‐acetyl‐D ‐mannosamine (ManNAc) by whole cells. The biotransformation utilized Escherichia coli cells (Neu5Ac aldolase), Pseudomonas stutzeri cells (lactate oxidase components), GlcNAc/ManNAc and lactate. By this process, 18.32±0.56 g/liter Neu5Ac were obtained from 65.61±2.70 g/liter lactate as an initial substrate input. Neu5Ac (98.4±0.4 % purity, 80.87±0.79 % recovery yield) was purified by anionic exchange chromatography. Our results demonstrate that the reported Neu5Ac biosynthetic process can compare favorably with natural product extraction or chemical synthesis processes. 相似文献
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Dr. Craig A. Coburn Dr. Peter T. Meinke Wei Chang Dr. Christine M. Fandozzi Donald J. Graham Dr. Bin Hu Qian Huang Dr. Stacia Kargman Dr. Joseph Kozlowski Dr. Rong Liu Dr. John A. McCauley Dr. Amin A. Nomeir Dr. Richard M. Soll Dr. Joseph P. Vacca Dr. Dahai Wang Dr. Hao Wu Dr. Bin Zhong Dr. David B. Olsen Dr. Steven W. Ludmerer 《ChemMedChem》2013,8(12):1930-1940
The NS5A protein plays a critical role in the replication of HCV and has been the focus of numerous research efforts over the past few years. NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays, making them attractive components for inclusion in all oral combination regimens. Early work in the NS5A arena led to the discovery of our first clinical candidate, MK‐4882 [2‐((S)‐pyrrolidin‐2‐yl)‐5‐(2‐(4‐(5‐((S)‐pyrrolidin‐2‐yl)‐1H‐imidazol‐2‐yl)phenyl)benzofuran‐5‐yl)‐1H‐imidazole]. While preclinical proof‐of‐concept studies in HCV‐infected chimpanzees harboring chronic genotype 1 infections resulted in significant decreases in viral load after both single‐ and multiple‐dose treatments, viral breakthrough proved to be a concern, thus necessitating the development of compounds with increased potency against a number of genotypes and NS5A resistance mutations. Modification of the MK‐4882 core scaffold by introduction of a cyclic constraint afforded a series of tetracyclic inhibitors, which showed improved virologic profiles. Herein we describe the research efforts that led to the discovery of MK‐8742, a tetracyclic indole‐based NS5A inhibitor, which is currently in phase 2b clinical trials as part of an all‐oral, interferon‐free regimen for the treatment of HCV infection. 相似文献
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The Fight against the Influenza A Virus H1N1: Synthesis,Molecular Modeling,and Biological Evaluation of Benzofurazan Derivatives as Viral RNA Polymerase Inhibitors 下载免费PDF全文
Dr. Mafalda Pagano Dr. Daniele Castagnolo Dr. Martina Bernardini Anna Lucia Fallacara Ilaria Laurenzana Davide Deodato Dr. Ulrich Kessler Dr. Beatrice Pilger Dr. Lilli Stergiou Dr. Stephan Strunze Dr. Cristina Tintori Prof. Maurizio Botta 《ChemMedChem》2014,9(1):129-150
The influenza RNA polymerase complex, which consists of the three subunits PA, PB1, and PB2, is a promising target for the development of new antiviral drugs. A large library of benzofurazan compounds was synthesized and assayed against influenza virus A/WSN/33 (H1N1). Most of the new derivatives were found to act by inhibiting the viral RNA polymerase complex through disruption of the complex formed between subunits PA and PB1. Docking studies were also performed to elucidate the binding mode of benzofurazans within the PB1 binding site in PA and to identify amino acids involved in their mechanism of action. The predicted binding pose is fully consistent with the biological data and lays the foundation for the rational development of more effective PA–PB1 inhibitors. 相似文献
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West Nile virus (WNV), a member of the Flaviviridae family, is a mosquito‐borne pathogen that causes a large number of human infections each year. There are currently no vaccines or antiviral therapies available for human use against WNV. Therefore, efforts to develop new chemotherapeutics against this virus are highly desired. In this study, a WNV NS2B–NS3 protease inhibitor with a 1,3,4,5‐tetrasubstituted 1H‐pyrrol‐2(5H)‐one scaffold was identified by screening a small library of nonpeptidic compounds. Optimization of this initial hit by the synthesis and screening of a focused library of compounds with this scaffold led to the identification of a novel uncompetitive inhibitor ((?)‐ 1a16 , IC50=2.2±0.7 μM ) of the WNV NS2B–NS3 protease. Molecular docking of the chiral compound onto the WNV protease indicates that the R enantiomer of 1a16 interferes with the productive interactions between the NS2B cofactor and the NS3 protease domain and is thus the preferred isomer for inhibition of the WNV NS2B–NS3 protease. 相似文献
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Dr. Stefan Peukert Dr. Feng He Miao Dai Rui Zhang Yingchuan Sun Dr. Karen Miller‐Moslin Michael McEwan Dr. Bharat Lagu Kate Wang Dr. Naeem Yusuff Aaron Bourret Arun Ramamurthy Dr. Wieslawa Maniara Adam Amaral Anthony Vattay Anlai Wang Ribo Guo Jing Yuan John Green Dr. Juliet Williams Dr. Silvia Buonamici Dr. Joseph F. Kelleher III Dr. Marion Dorsch 《ChemMedChem》2013,8(8):1261-1265
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Synthesis and Biological Evaluation of Pyrrolo[2,1‐f][1,2,4]triazine C‐Nucleosides with a Ribose, 2′‐Deoxyribose,and 2′,3′‐Dideoxyribose Sugar Moiety 下载免费PDF全文
Qingfeng Li Prof. Eveline Lescrinier Dr. Elisabetta Groaz Leentje Persoons Prof. Dirk Daelemans Prof. Piet Herdewijn Dr. Steven De Jonghe 《ChemMedChem》2018,13(1):97-104
The synthesis of hitherto unknown pyrrolo[2,1‐f][1,2,4]triazine C‐nucleosides is described. Structural variations (chlorine, bromine, iodine, and cyano groups) were introduced at position 7 of 4‐aza‐7,9‐dideazaadenine. In addition, pyrrolo[2,1‐f][1,2,4]triazine C‐nucleosides bearing a 2′‐deoxy‐, 2′,3′‐dideoxy‐, and 2′,3′‐dehydrodideoxyribose moiety were also prepared. Among these analogues, the pyrrolo[2,1‐f][1,2,4]triazine C‐ribonucleosides with either a hydrogen atom or cyano group at position 7 of the nucleobase displayed potent cytotoxic activity in a panel of various cancer cell lines. 相似文献