共查询到20条相似文献,搜索用时 15 毫秒
1.
Design,Synthesis, and Biological Evaluation of 1,3‐Diarylpropenones as Dual Inhibitors of HIV‐1 Reverse Transcriptase 下载免费PDF全文
Dr. Rita Meleddu Dr. Valeria Cannas Dr. Simona Distinto Dr. Giorgia Sarais Dr. Claudia Del Vecchio Dr. Francesca Esposito Dr. Giulia Bianco Dr. Angela Corona Dr. Filippo Cottiglia Prof. Stefano Alcaro Prof. Cristina Parolin Dr. Anna Artese Dr. Daniela Scalise Prof. Massimo Fresta Dr. Antonella Arridu Dr. Francesco Ortuso Prof. Elias Maccioni Prof. Enzo Tramontano 《ChemMedChem》2014,9(8):1869-1879
2.
Jianmei Cui Jinshan Jin Arpana Sagwal Chaudhary Ying‐hsin Hsieh Hao Zhang Chaofeng Dai Krishna Damera Weixuan Chen Phang C. Tai Binghe Wang 《ChemMedChem》2016,11(1):43-56
SecA, a key component of the bacterial Sec‐dependent secretion pathway, is an attractive target for the development of new antimicrobial agents. Through a combination of virtual screening and experimental exploration of the surrounding chemical space, we identified a hit bistriazole SecA inhibitor, SCA‐21, and studied a series of analogues by systematic dissections of the core scaffold. Evaluation of these analogues allowed us to establish an initial structure–activity relationship in SecA inhibition. The best compounds in this group are potent inhibitors of SecA‐dependent protein‐conducting channel activity and protein translocation activity at low‐ to sub‐micromolar concentrations. They also have minimal inhibitory concentration (MIC) values against various strains of bacteria that correlate well with the SecA and protein translocation inhibition data. These compounds are effective against methicillin‐resistant Staphylococcus aureus strains with various levels of efflux pump activity, indicating the capacity of SecA inhibitors to null the effect of multidrug resistance. Results from studies of drug‐affinity‐responsive target stability and protein pull‐down assays are consistent with SecA as a target for these compounds. 相似文献
3.
Design of gem‐Difluoro‐bis‐Tetrahydrofuran as P2 Ligand for HIV‐1 Protease Inhibitors to Improve Brain Penetration: Synthesis,X‐ray Studies,and Biological Evaluation 下载免费PDF全文
Prof. Dr. Arun K. Ghosh Sofiya Yashchuk Akira Mizuno Nilanjana Chakraborty Johnson Agniswamy Yuan‐Fang Wang Manabu Aoki Pedro Miguel Salcedo Gomez Masayuki Amano Prof. Irene T. Weber Dr. Hiroaki Mitsuya 《ChemMedChem》2015,10(1):107-115
The structure‐based design, synthesis, biological evaluation, and X‐ray structural studies of fluorine‐containing HIV‐1 protease inhibitors are described. The synthesis of both enantiomers of the gem‐difluoro‐bis‐THF ligands was carried out in a stereoselective manner using a Reformatskii–Claisen reaction as the key step. Optically active ligands were converted into protease inhibitors. Two of these inhibitors, (3R,3aS,6aS)‐4,4‐difluorohexahydrofuro[2,3‐b]furan‐3‐yl(2S,3R)‐3‐hydroxy‐4‐((N‐isobutyl‐4‐methoxyphenyl)sulfonamido)‐1‐phenylbutan‐2‐yl) carbamate ( 3 ) and (3R,3aS,6aS)‐4,4‐difluorohexahydrofuro[2,3‐b]furan‐3‐yl(2S,3R)‐3‐hydroxy‐4‐((N‐isobutyl‐4‐aminophenyl)sulfonamido)phenylbutan‐2‐yl) carbamate ( 4 ), exhibited HIV‐1 protease inhibitory Ki values in the picomolar range. Both 3 and 4 showed very potent antiviral activity, with respective EC50 values of 0.8 and 3.1 nM against the laboratory strain HIV‐1LAI. The two inhibitors exhibited better lipophilicity profiles than darunavir, and also showed much improved blood–brain barrier permeability in an in vitro model. A high‐resolution X‐ray structure of inhibitor 4 in complex with HIV‐1 protease was determined, revealing that the fluorinated ligand makes extensive interactions with the S2 subsite of HIV‐1 protease, including hydrogen bonding interactions with the protease backbone atoms. Moreover, both fluorine atoms on the bis‐THF ligand formed strong interactions with the flap Gly 48 carbonyl oxygen atom. 相似文献
4.
Yong‐Hong Liang Xiao‐Qing Feng Zhao‐Sen Zeng Fen‐Er Chen Prof. Dr. Jan Balzarini Prof. Dr. Christophe Pannecouque Prof. Dr. Erik De Clercq Prof. Dr. 《ChemMedChem》2009,4(9):1537-1545
A series of 38 2‐naphthyl‐substituted diarylpyrimidine (DAPY) analogues, characterized by various substitution patterns on the pyrimidine and naphthalene rings, was synthesized in a straightforward fashion by means of parallel synthesis and evaluated as inhibitors of the HIV‐1 wild‐type and double mutant (K103N+Y181C) strains. Most of the compounds displayed strong activity against wild‐type HIV‐1. The most active compound, with a cyano group at position C6 on the naphthalene ring, exhibited activity against wild‐type HIV‐1 with an EC50 value of 0.002 μM and against the double mutant strain with an EC50 value of 0.24 μM ; the selectivity index (SI) against wild‐type is >180 000, the highest SI value among DAPY analogues. The structure–activity relationship (SAR) of the newly synthesized DAPYs is presented herein. 相似文献
5.
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
6.
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
7.
Dr. Silvia Meneghesso Dr. Andrea Brancale Prof. Jan Balzarini Prof. Lieve Naesens Prof. Christopher McGuigan 《ChemMedChem》2013,8(3):415-425
2′‐Fluoro‐2′‐deoxyguanosine has been reported to have potent anti‐influenza virus activity in vitro and in vivo. Herein we describe the synthesis and biological evaluation of 6‐modified 2′‐fluoro‐2′‐deoxyguanosine analogues and their corresponding phosphoramidate ProTides as potential anti‐influenza virus agents. Whereas the parent nucleosides were devoid of antiviral activity in two different cellular assays, the 5′‐O‐naphthyl(methoxy‐L ‐alaninyl) ProTide derivatives of 6‐O‐methyl‐2′‐fluoro‐2′‐deoxyguanosine, 6‐O‐ethyl‐2′‐fluoro‐2′‐deoxyguanosine, and 2′‐deoxy‐2′‐fluoro‐6‐chloroguanosine, and the 5′‐O‐naphthyl(ethoxy‐L ‐alaninyl) ProTide of 6‐O‐ethyl‐2′‐fluoro‐2′‐deoxyguanosine displayed antiviral EC99 values of ~12 μM . The antiviral results are supported by metabolism studies. Rapid conversion into the L ‐alaninyl metabolite and then 6‐modified 2′‐fluoro‐2′‐deoxyguanosine 5′‐monophosphate was observed in enzymatic assays with yeast carboxypeptidase Y or crude cell lysate. Evidence for efficient removal of the 6‐substituent on the guanine part was provided by enzymatic studies with adenosine deaminase, and by molecular modeling of the nucleoside 5′‐monophosphates in the catalytic site of a model of ADAL1, thus indicating the utility of the double prodrug concept. 相似文献
8.
Dr. Jianmei Cui Dr. Jinshan Jin Dr. Ying‐Hsin Hsieh Dr. Hsiuchin Yang Dr. Bowen Ke Dr. Krishna Damera Dr. Phang C. Tai Dr. Binghe Wang 《ChemMedChem》2013,8(8):1384-1393
SecA, a key component of bacterial Sec‐dependent secretion pathway, is an attractive target for exploring novel antimicrobials. Rose bengal (RB), a polyhalogenated fluorescein derivative, was found from our previous study as a potent SecA inhibitor. Here we describe the synthesis and structure–activity relationships (SAR) of 23 RB analogues that were designed by systematical dissection of RB. Evaluation of these analogues allowed us to establish an initial SAR in SecA inhibition. The antimicrobial effects of these SecA inhibitors are confirmed in experiments using E. coli and B. subtilis. 相似文献
9.
Computer‐Guided Design,Synthesis, and Biological Evaluation of Quinoxalinebisarylureas as FLT3 Inhibitors 下载免费PDF全文
Stefan Göring Dennis Bensinger Dr. Eva C. Naumann Prof. Dr. Boris Schmidt 《ChemMedChem》2015,10(3):511-522
Activating mutations of FMS‐like tyrosine kinase 3 (FLT3) are present in ~30 % of patients with acute myeloid leukemia (AML) and are associated with poor prognosis. Point mutations in the tyrosine kinase domain (TKD) are observed as primary mutations or are acquired as secondary mutations in FLT3 with internal tandem duplications (ITDs) after treatment with tyrosine kinase inhibitors (TKIs). Although dozens of potent inhibitors against FLT3 ITD have been reported, activating TKD point mutations, especially at residues F691 and D835, remain the leading cause for therapy resistance, highlighting the consistent need for new potent inhibitors. Herein we report the identification and characterization of novel quinoxaline‐based FLT3 inhibitors. We used the pharmacophore features of diverse known inhibitors as a starting point for a new optimization algorithm for type II TKIs, starting from an in silico library pharmacophore search and induced‐fit docking in the known FLT3 structure. This led to the design of a set of diverse quinoxalinebisarylureas, which were profiled in an FLT3 kinase activity assay. The most promising compounds were further evaluated in a zebrafish embryo phenotype assay. 相似文献
10.
Linrong Zhu Dr. Yuanyuan Li Dr. Ling Qiu Dr. Mingbo Su Prof. Xin Wang Chunmei Xia Dr. Yi Qu Prof. Jingya Li Prof. Jia Li Prof. Bing Xiong Prof. Jingkang Shen 《ChemMedChem》2013,8(7):1104-1116
The worldwide prevalence of diabetes has spurred numerous studies on the development of new antidiabetic medicines. As a result, dipeptidyl peptidase IV (DPP4) has been recognized as a validated target. In our efforts to discover new DPP4 inhibitors, we analyzed the complexed structures of DPP4 available in Protein Data Bank and designed a series of triazole compounds. After enzyme activity assays and crystallographic verification of the binding interaction patterns, we found that the triazole compounds can inhibit DPP4 with micromolar IC50 values. Liver microsome stability and cytochrome P450 metabolic tests were performed on this series, revealing undesirable pharmacokinetic profiles for the triazole compounds. To overcome this liability, we substituted the triazole ring with an amide or urea group to produce a new series of DPP4 inhibitors. Based on its enzyme activity, metabolic stability, and selectivity over DPP8 and DPP9, we selected compound 21 r for further study of its in vivo effects in mice using an oral glucose tolerance test (OGTT). The results show that 21 r has efficacy similar to that of sitagliptin at a dose of 3 mg kg?1. The crystal structure of 21 r bound to DPP4 also reveals that the trifluoromethyl group is directed toward a subpocket different from the subsite bound by sitagliptin, providing clues for the design of new DPP4 inhibitors. 相似文献
11.
Loek T. M. van Wandelen Dr. Jeroen van Ameijde Ahmed S. A. Mady Angelique E. M. Wammes Alois Bode Dr. Alex J. Poot Dr. Rob Ruijtenbeek Prof. Dr. Rob M. J. Liskamp 《ChemMedChem》2012,7(12):2113-2121
Kinases present an attractive target for drug development, since they are involved in vital cellular processes and are implicated in a variety of diseases, such as cancer and diabetes. However, obtaining selectivity for a specific kinase over others is difficult since many current kinase inhibitors exclusively target the highly conserved kinase ATP binding domain. Previously, a microarray‐based strategy to discover so‐called bisubstrate‐based inhibitors that target the more specific peptide binding groove in addition to the ATP binding site was described. One attractive feature of this strategy is the opportunity to tune the selectivity of these inhibitors by systematically varying components. In an extension to this previous work, this study explores the potential of this guided selectivity modulation, leading to a series of inhibitors with different selectivity profiles against highly homologous protein kinase C (PKC) isozymes. Of the inhibitors studied, most exhibited improved potency and selectivity compared with their constituent parts. Furthermore, the selectivity was found to be tunable either through modification of the pseudosubstrate peptide (peptide binding groove) or the ATP‐competitive part (ATP binding site). In a number of cases, the selectivity of the construct could be predicted from the initial peptide substrate profiling experiment. Since this strategy is applicable to all kinase sets, it could be used to rapidly develop uniquely selective inhibitors. 相似文献
12.
The Discovery of Potent Nonstructural Protein 5A (NS5A) Inhibitors with a Unique Resistance Profile—Part 2 下载免费PDF全文
Florian Wakenhut Thien Duc Tran Dr. Chris Pickford Stephen Shaw Dr. Mike Westby Caroline Smith‐Burchnell Lesa Watson Michael Paradowski Dr. Jared Milbank David Stonehouse Dr. Kathy Cheung Dr. Robert Wybrow Dr. Felice Daverio Dr. Samuel Crook Keith Statham Dr. David Leese Dr. Darren Stead Fiona Adam Duncan Hay Dr. Lee R. Roberts Jean‐Yves Chiva Carly Nichols Dr. David C. Blakemore Gilles H. Goetz Dr. Ye Che Iain Gardner Satish Dayal Dr. Andrew Pike Rob Webster Dr. David C. Pryde 《ChemMedChem》2014,9(7):1387-1396
In ongoing studies towards novel hepatitis C virus (HCV) therapeutics, inhibitors of nonstructural protein 5A (NS5A) were evaluated. Specifically, starting from previously reported lead compounds, peripheral substitution patterns of a series of biaryl‐linked pyrrolidine NS5A replication complex inhibitors were probed and structure–activity relationships were elucidated. Using molecular modelling and a supercritical fluid chromatographic (SFC) technique, intramolecular H‐bonding and peripheral functional group topology were evaluated as key determinants of activity and membrane permeability. The novel compounds exhibited retained potency as compared with the lead compounds, and also showed promising results against a panel of resistance viruses. Together, the results of the study take us a step closer towards understanding the potency of daclatasvir, a clinical candidate upon which the compounds were based, and to designing improved analogues as second‐generation antiviral agents targeting NS5A. 相似文献
13.
14.
15.
Jose Ignacio Martin Hernando Dr. Jesus Maria Ontoria Dr. Savina Malancona Barbara Attenni Fabrizio Fiore Fabio Bonelli Uwe Koch Dr. Stefania Di Marco Dr. Stefania Colarusso Simona Ponzi Nadia Gennari Sue Ellen Vignetti Maria del Rosario Rico Ferreira Dr. Jörg Habermann Dr. Michael Rowley Dr. Frank Narjes Dr. 《ChemMedChem》2009,4(10):1695-1713
Infections caused by the hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The NS5B polymerase of HCV is responsible for the replication of viral RNA and has been a prime target in the search for novel treatment options. We had discovered allosteric finger‐loop inhibitors based on a thieno[3,2‐b]pyrrole scaffold as an alternative to the related indole inhibitors. Optimization of the thienopyrrole series led to several N‐acetamides with submicromolar potency in the cell‐based replicon assay, but they lacked oral bioavailability in rats. By linking the N4‐position to the ortho‐position of the C5‐aryl group, we were able to identify the tetracyclic thienopyrrole 40 , which displayed a favorable pharmacokinetic profile in rats and dogs and is equipotent with recently disclosed finger‐loop inhibitors based on an indole scaffold. 相似文献
16.
Li‐Mei Gao Dr. Sheng Tang Dr. Yan‐Xiang Wang Dr. Rong‐Mei Gao Dr. Xin Zhang Dr. Zong‐Gen Peng Jian‐Rui Li Prof. Jian‐Dong Jiang Prof. Yu‐Huan Li Prof. Dan‐Qing Song 《ChemMedChem》2013,8(9):1545-1553
A series of novel N‐substituted sophocarpinic acid derivatives was designed, synthesized, and evaluated for their anti‐enteroviral activities against coxsackievirus type B3 (CVB3) and coxsackievirus type B6 (CVB6) in Vero cells. Structure–activity relationship analysis revealed that the introduction of a benzenesulfonyl moiety on the 12‐nitrogen atom in (E)‐β,γ‐sophocarpinic acid might significantly enhance anti‐CVB3 activity. Among the derivatives, (E)‐12‐N‐(m‐cyanobenzenesulfonyl)‐β,γ‐sophocarpinic acid ( 11 m ), possessing a meta‐cyanobenzenesulfonyl group, exhibited potent activity against CVB3 with a selectivity index (SI) of 107. Furthermore, compound 11 m also showed a good oral pharmacokinetic profile, with an AUC value of 7.29 μM h?1 in rats, and good safety through the oral route in mice, with an LD50 value of >1000 mg kg?1; these values suggest a druggable characteristic. Therefore, compound 11 m was selected for further investigation as a promising CVB3 inhibitor. We consider (E)‐β,γ‐N‐(benzenesulfonyl)sophocarpinic acids to be a novel class of anti‐CVB3 agents. 相似文献
17.
Luke R. Odell Dr. Ngoc Chau Anna Mariana Mark E. Graham Dr. Phillip J. Robinson Prof. Adam McCluskey Prof. 《ChemMedChem》2009,4(7):1182-1188
Probing the dynamin binding site : Bis‐tyrphostin ( 1 , Bis‐T), is a potent inhibitor of the phospholipid‐stimulated GTPase activity of dynamin I. Analogues of Bis‐T have significant potential as a biological probes for the dissection of endocytic pathways. Bis‐T‐derived compounds were synthesised and evaluated for their ability to inhibit the GTPase activity of dynamin I. Two analogues ( 23 and 24 ) represent the first asymmetrically substituted Bis‐T analogues to retain dynamin inhibition.
18.
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
19.
20.
The Discovery of Potent Nonstructural Protein 5A (NS5A) Inhibitors with a Unique Resistance Profile—Part 1 下载免费PDF全文
Thien Duc Tran Florian Wakenhut Dr. Chris Pickford Stephen Shaw Dr. Mike Westby Caroline Smith‐Burchnell Lesa Watson Michael Paradowski Dr. Jared Milbank Dr. Rebecca A. Brimage Rebecca Halstead Dr. Rebecca Glen Dr. Craig P. Wilson Fiona Adam Duncan Hay Jean‐Yves Chiva Carly Nichols Dr. David C. Blakemore Iain Gardner Satish Dayal Dr. Andrew Pike Rob Webster Dr. David C. Pryde 《ChemMedChem》2014,9(7):1378-1386
Nonstructural protein 5A (NS5A) represents a novel target for the treatment of hepatitis C virus (HCV). Daclatasvir, recently reported by Bristol–Myers–Squibb, is a potent NS5A inhibitor currently under investigation in phase 3 clinical trials. While the performance of daclatasvir has been impressive, the emergence of resistance could prove problematic and as such, improved analogues are being sought. By varying the biphenyl‐imidazole unit of daclatasvir, novel inhibitors of HCV NS5A were identified with an improved resistance profile against mutant strains of the virus while retaining the picomolar potency of daclatasvir. One compound in particular, methyl ((S)‐1‐((S)‐2‐(4‐(4‐(6‐(2‐((S)‐1‐((methoxycarbonyl)‐L ‐valyl)pyrrolidin‐2‐yl)‐1H‐imidazol‐5‐yl)quinoxalin‐2‐yl)phenyl)‐1H‐imidazol‐2‐yl)pyrrolidin‐1‐yl)‐3‐methyl‐1‐oxobutan‐2‐yl)carbamate ( 17 ), exhibited very promising activity and showed good absorption and a long predicted human pharmacokinetic half‐life. This compound represents a promising lead that warrants further evaluation. 相似文献