共查询到20条相似文献,搜索用时 31 毫秒
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Ma XD Yang SQ Gu SX He QQ Chen FE De Clercq E Balzarini J Pannecouque C 《ChemMedChem》2011,6(12):2225-2232
A series of novel diarylpyrimidines (DAPYs) with a ketone hydrazone substituent on the methylene linker between the pyrimidine nucleus and the aryl moiety at the C‐4 position were synthesized, and their antiviral activity against human immunodeficiency virus (HIV)‐1 in MT‐4 cells was evaluated. Most compounds of this class exhibited excellent activity against wild‐type HIV‐1, with EC50 values in the range of 1.7–13.2 nM . Of these compounds, 2‐bromophenyl‐2‐[(4‐cyanophenyl)amino]‐4‐pyrimidinone hydrazone ( 9 k ) displayed the most potent anti‐HIV‐1 activity (EC50=1.7±0.6 nM ), with excellent selectivity for infected over uninfected cells (SI=5762). In addition, the 4‐methyl phenyl analogue 9 d (EC50=2.4±0.2 nM , SI=18461) showed broad spectrum HIV inhibitory activity, with EC50 values of 2.4±0.2 nM against wild‐type HIV‐1, 5.3±0.4 μM against HIV‐1 double‐mutated strain RES056 (K103N+Y181C), and 5.5 μM against HIV‐2 ROD strain. Furthermore, structure–activity relationship (SAR) data and molecular modeling results for these compounds are also discussed. 相似文献
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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
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Structure‐Based Design of New KSP‐Eg5 Inhibitors Assisted by a Targeted Multicomponent Reaction
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Carlos Carbajales Dr. Miguel Ángel Prado Dr. Hugo Gutiérrez‐de‐Terán Ángel Cores Dr. Jhonny Azuaje Dr. Silvia Novio Prof. María Jesús Nuñez Dr. Belén Fernández‐García Prof. Eddy Sotelo Prof. Xerardo García‐Mera Prof. Pedro Sánchez‐Lazo Prof. Manuel Freire‐Garabal Prof. Alberto Coelho 《Chembiochem : a European journal of chemical biology》2014,15(10):1471-1480
An integrated multidisciplinary approach that combined structure‐based drug design, multicomponent reaction synthetic approaches and functional characterization in enzymatic and cell assays led to the discovery of new kinesin spindle protein (KSP) inhibitors with antiproliferative activity. A focused library of new benzimidazoles obtained by a Ugi+Boc removal/cyclization reaction sequence generated low‐micromolar‐range KSP inhibitors as promising anticancer prototypes. The design and functional studies of the new chemotypes were assessed by computational modeling and molecular biology techniques. The most active compounds— 20 (IC50=1.49 μM , EC50=3.63 μM ) and 22 (IC50=1.37 μM , EC50=6.90 μM )—were synthesized with high efficiency by taking advantage of the multicomponent reactions. 相似文献
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Stephen Patterson Dr. Deuan C. Jones Dr. Emma J. Shanks Dr. Julie A. Frearson Prof. Ian H. Gilbert Prof. Paul G. Wyatt Prof. Alan H. Fairlamb Prof. 《ChemMedChem》2009,4(8):1341-1353
Thirty two analogues of phencyclidine were synthesised and tested as inhibitors of trypanothione reductase (TryR), a potential drug target in trypanosome and leishmania parasites. The lead compound BTCP ( 1 , 1‐(1‐benzo[b]thiophen‐2‐yl‐cyclohexyl) piperidine) was found to be a competitive inhibitor of the enzyme (Ki=1 μM ) and biologically active against bloodstream T. brucei (EC50=10 μM ), but with poor selectivity against mammalian MRC5 cells (EC50=29 μM ). Analogues with improved enzymatic and biological activity were obtained. The structure–activity relationships of this novel series are discussed. 相似文献
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Activity of Fluorine‐Containing Analogues of WC‐9 and Structurally Related Analogues against Two Intracellular Parasites: Trypanosoma cruzi and Toxoplasma gondii
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María N. Chao Catherine Li Melissa Storey Dr. Bruno N. Falcone Dr. Sergio H. Szajnman Prof. Dr. Sergio M. Bonesi Prof. Dr. Roberto Docampo Prof. Dr. Silvia N. J. Moreno Prof. Dr. Juan B. Rodriguez 《ChemMedChem》2016,11(24):2690-2702
Two obligate intracellular parasites, Trypanosoma cruzi, the agent of Chagas disease, and Toxoplasma gondii, an agent of toxoplasmosis, upregulate the mevalonate pathway of their host cells upon infection, which suggests that this host pathway could be a potential drug target. In this work, a number of compounds structurally related to WC‐9 (4‐phenoxyphenoxyethyl thiocyanate), a known squalene synthase inhibitor, were designed, synthesized, and evaluated for their effect on T. cruzi and T. gondii growth in tissue culture cells. Two fluorine‐containing derivatives, the 3‐(3‐fluorophenoxy)‐ and 3‐(4‐fluorophenoxy)phenoxyethyl thiocyanates, exhibited half‐maximal effective concentration (EC50) values of 1.6 and 4.9 μm , respectively, against tachyzoites of T. gondii, whereas they showed similar potency to WC‐9 against intracellular T. cruzi (EC50 values of 5.4 and 5.7 μm , respectively). In addition, 2‐[3‐ (phenoxy)phenoxyethylthio]ethyl‐1,1‐bisphosphonate, which is a hybrid inhibitor containing 3‐phenoxyphenoxy and bisphosphonate groups, has activity against T. gondii proliferation at sub‐micromolar levels (EC50=0.7 μm ), which suggests a combined inhibitory effect of the two functional groups. 相似文献
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Dr. Tony Fröhlich Christina Mai Roman P. Bogautdinov Prof. Dr. Svetlana N. Morozkina Prof. Dr. Alexander G. Shavva Prof. Dr. Oliver Friedrich Dr. Daniel F. Gilbert Prof. Dr. Svetlana B. Tsogoeva 《ChemMedChem》2020,15(15):1473-1479
In the search for new and effective treatments of breast and prostate cancer, a series of hybrid compounds based on tamoxifen, estrogens, and artemisinin were successfully synthesized and analyzed for their in vitro activities against human prostate (PC-3) and breast cancer (MCF-7) cell lines. Most of the hybrid compounds exhibit a strong anticancer activity against both cancer cell lines – for example, EC50 (PC-3) down to 1.07 μM, and EC50 (MCF-7) down to 2.08 μM – thus showing higher activities than their parent compounds 4-hydroxytamoxifen (afimoxifene, 7 ; EC50=75.1 (PC-3) and 19.3 μM (MCF-7)), dihydroartemisinin ( 2 ; EC50=263.6 (PC-3) and 49.3 μM (MCF-7)), and artesunic acid ( 3 ; EC50=195.1 (PC-3) and 32.0 μM (MCF-7)). The most potent compounds were the estrogen-artemisinin hybrids 27 and 28 (EC50=1.18 and 1.07 μM, respectively) against prostate cancer, and hybrid 23 (EC50=2.08 μM) against breast cancer. These findings demonstrate the high potential of hybridization of artemisinin and estrogens to further improve their anticancer activities and to produce synergistic effects between linked pharmacophores. 相似文献
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Monoamine Oxidase (MAO) Inhibitory Activity: 3‐Phenylcoumarins versus 4‐Hydroxy‐3‐phenylcoumarins
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Dr. Giovanna L. Delogu Dr. Silvia Serra Dr. Elias Quezada Prof. Eugenio Uriarte Dr. Santiago Vilar Dr. Nicholas P. Tatonetti Dr. Dolores Viña 《ChemMedChem》2014,9(8):1672-1676
Monoamine oxidase (MAO) is a useful target in the treatment of neurodegenerative diseases and depressive disorders. Both isoforms, MAO‐A and MAO‐B, are known to play critical roles in disease progression, and as such, the identification of novel, potent and selective inhibitors is an important research goal. Here, two series of 3‐phenylcoumarin derivatives were synthesized and evaluated against MAO‐A and MAO‐B. Most of the compounds tested acted preferentially on MAO‐B, with IC50 values in the micromolar to nanomolar range. Only 6‐chloro‐4‐hydroxy‐3‐(2’‐hydroxyphenyl)coumarin exhibited activity against the MAO‐A isoform, while still retaining good selectivity for MAO‐B. 6‐Chloro‐3‐phenylcoumarins unsubstituted at the 4 position were found to be more active as MAO‐B inhibitors than the corresponding 4‐hydroxylated coumarins. For 4‐unsubstituted coumarins, meta and para positions on the 3‐phenyl ring seem to be the most favorable for substitution. Molecular docking simulations were used to explain the observed hMAO‐B structure–activity relationships for this type of compound. 6‐Chloro‐3‐(3’‐methoxyphenyl)coumarin was the most active compound identified (IC50=0.001 μM ) and is several times more potent and selective than the reference compound, R‐(?)‐deprenyl hydrochloride. This compound represents a novel tool for the further investigation of the therapeutic potential of MAO‐B inhibitors. 相似文献
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Dr. Debasmita Saha Dr. Katie Rose Ryan Dr. Naga Rajiv Lakkaniga Erica Lane Smith Dr. Brendan Frett 《ChemMedChem》2021,16(10):1605-1608
A fragment-based drug-discovery approach was used on a pyrazoloadenine fragment library to uncover new molecules that target the RET (REarranged during Transfection) oncoprotein, which is a driver oncoprotein in ∼2 % of non-small-cell lung cancers. The fragment library was screened against the RET kinase and LC-2/ad (RET-driven), KM-12 (TRKA-driven matched control) and A549 (cytotoxic control) cells to identify selective scaffolds that could inhibit RET-driven growth. An unsubstituted pyrazoloadenine fragment was found to be active on RET in a biochemical assay, but reduced cell viability in non-RET-driven cell lines (EC50=1 and 3 μM, respectively). To increase selectivity for RET, the pyrazoloadenine was modeled in the RET active site, and two domains were identified that were probed with pyrazoloadenine fragment derivatives to improve RET affinity. Scaffolds at each domain were merged to generate a novel lead compound, 8 p , which exhibited improved activity and selectivity for the RET oncoprotein (A549 EC50=5.92 μM, LC-2/ad EC50=0.016 μM, RET IC50=0.000326 μM). 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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Molecular‐Target‐Based Anticancer Photosensitizer: Synthesis and in vitro Photodynamic Activity of Erlotinib–Zinc(II) Phthalocyanine Conjugates
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Dr. Feng‐Ling Zhang Qi Huang Prof. Jian‐Yong Liu Prof. Ming‐Dong Huang Prof. Jin‐Ping Xue 《ChemMedChem》2015,10(2):312-320
Targeted photodynamic therapy is a new promising therapeutic strategy to overcome growing problems in contemporary medicine, such as drug toxicity and drug resistance. A series of erlotinib–zinc(II) phthalocyanine conjugates were designed and synthesized. Compared with unsubstituted zinc(II) phthalocyanine, these conjugates can successfully target EGFR‐overexpressing cancer cells owing to the presence of the small molecular‐target‐based anticancer agent erlotinib. All conjugates were found to be essentially non‐cytotoxic in the absence of light (up to 50 μM ), but upon illumination, they show significantly high photo‐cytotoxicity toward HepG2 cells, with IC50 values as low as 9.61–91.77 nM under a rather low light dose (λ=670 nm, 1.5 J cm?2). Structure–activity relationships for these conjugates were assessed by determining their photophysical/photochemical properties, cellular uptake, and in vitro photodynamic activities. The results show that these conjugates are highly promising antitumor agents for molecular‐target‐based photodynamic therapy. 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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Beihua Bao Zheng Meng Nianguang Li Zhengjie Meng Li Zhang Yudan Cao Weifeng Yao Mingqiu Shan Anwei Ding 《International journal of molecular sciences》2013,14(8):17193-17203
A series of schizonepetin derivatives have been designed and synthesized in order to obtain potent antivirus agents. The antiviral activity against HSV-1 and influenza virus H3N2 as well as the cytotoxicity of these derivatives was evaluated by using cytopathic effect (CPE) inhibition assay in vitro. Compounds M2, M4, M5 and M34 showed higher inhibitory activity against HSV-1 virus with the TC50 values being in micromole. Compounds M28, M33, and M35 showed higher inhibitory activity against influenza virus H3N2 with their TC50 values being 96.4, 71.0 and 75.4 μM, respectively. Preliminary biological activity evaluation indicated that the anti-H3N2 and anti-HSV-1 activities improved obviously through the introduction of halogen into the structure of schizonepetin. 相似文献
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Structure–Activity Relationship of Tumor‐Selective 5‐Substituted 2‐Amino‐3‐carboxymethylthiophene Derivatives
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Dr. Joice Thomas Dr. Alenka Jejcic Peter Vervaeke Prof. Romeo Romagnoli Prof. Sandra Liekens Prof. Jan Balzarini Prof. Wim Dehaen 《ChemMedChem》2014,9(12):2744-2753
Methyl‐2‐amino‐5‐[2‐(4‐methoxyphenethyl)]thiophene‐3‐carboxylate ( 8 c ) is the prototype of a well‐defined class of tumor‐selective agents. Compound 8 c preferentially inhibited the proliferation of a number of tumor cell lines including many human T‐lymphoma/leukemia cells, but also several prostate, renal, central nervous system and liver tumor cell types. Instead, a broad variety of other tumor cell lines including B‐lymphomas and HeLa cells were not affected. The tumor selectivity (TS; selectivity index or preferential suppression of CEM lymphoma (IC50=0.90 μM ) versus HeLa tumor cell carcinoma (IC50=39 μM )) amounted up to ~43 for 8 c . At higher concentrations, the compound proved cytotoxic rather than cytostatic. The antiproliferative potency and selectivity of 8 c could be preserved by replacing the ethyl linker between the 2‐amino‐3‐carboxymethylthiophene and the substituted aryl by a thioalkyl but not by an oxyalkyl nor an aminoalkyl. Among >50 novel 8 c derivatives, the 5‐(4‐ethyl‐ and 4‐isopropylarylmethylthio)thiophene analogues, methyl‐2‐amino‐5‐((4‐ethylphenylthio)methyl)thiophene‐3‐carboxylate ( 13 m ) and methyl‐2‐amino‐5‐((4‐isopropylphenylthio)methyl)thiophene‐3‐carboxylate ( 13 n ), were more potent (IC50: 0.3–0.4 μM ) and selective (TS: 100–144) anti‐T‐lymphoma/leukemia agents than the prototype compound. 相似文献
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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
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Chuang HY Chang JY Lai MJ Kuo CC Lee HY Hsieh HP Chen YJ Chen LT Pan WY Liou JP 《ChemMedChem》2011,6(3):450-456
A series of novel 2‐amino‐3,4,5‐trimethoxybenzophenone analogues exhibited excellent activity as tubulin polymerization inhibitors by targeting the colchicine binding site of microtubules. The lead compound 17 exhibited an IC50 value of 1.6 μM , similar to that of combretastatin A‐4 (IC50=1.9 μM ). It also displayed remarkable anti‐proliferative activity, with IC50 values ranging from 7–16 nM against a variety of human cancer cell lines and one MDR(+) cancer cell line. SAR information indicated that the introduction of an amino group at the C2 position of benzophenone ring A and the C3’ position of benzophenone ring B play important roles in maximizing activity. 相似文献
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A novel lead compound for inhibition of the antibacterial drug target, glutamate racemase (GR), was optimized for both ligand efficiency and lipophilic efficiency. A previously developed hybrid molecular dynamics–docking and scoring scheme, FERM‐SMD, was used to predict relative potencies of potential derivatives prior to chemical synthesis. This scheme was successful in distinguishing between high‐ and low‐affinity binders with minimal experimental structural information, saving time and resources in the process. In vitro potency was increased approximately fourfold against GR from the model organism, B. subtilis. Lead derivatives show two‐ to fourfold increased antimicrobial potency over the parent scaffold. In addition, specificity toward B. subtilis over E. coli and S. aureus depends on the substituent added to the parent scaffold. Finally, insight was gained into the capacity for these compounds to reach the target enzyme in vivo using a bacterial cell wall lysis assay. The outcome of this study is a novel small‐molecule inhibitor of GR with the following characteristics: Ki=2.5 μM , LE=0.45 kcal mol?1 atom?1, LiPE=6.0, MIC50=260 μg mL?1 against B. subtilis, EC50, lysis=520 μg mL?1 against B. subtilis. 相似文献
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Discovery of a Small‐Molecule pBcl‐2 Inhibitor that Overcomes pBcl‐2‐Mediated Resistance to Apoptosis
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Dr. Ting Song Xiaoyan Yu Dr. Yubo Liu Dr. Xiangqian Li Gaobo Chai Dr. Zhichao Zhang 《Chembiochem : a European journal of chemical biology》2015,16(5):757-765
Although the role of Bcl‐2 phosphorylation is still under debate, it has been identified in a resistance mechanism to BH3 mimetics, for example ABT‐737 and S1 . We identified an S1 analogue, S1‐16 , as a small‐molecule inhibitor of pBcl‐2. S1‐16 efficiently kills EEE‐Bcl‐2 (a T69E, S70E, and S87E mutant mimicking phosphorylation)‐expressing HL‐60 cells and high endogenously expressing pBcl‐2 cells, by disrupting EEE‐Bcl‐2 or native pBcl‐2 interactions with Bax and Bak, followed by apoptosis. In vitro binding assays showed that S1‐16 binds to the BH3 binding groove of EEE‐Bcl‐2 (Kd=0.38 μM by ITC; IC50=0.16 μM by ELISA), as well as nonphosphorylated Bcl‐2 (npBcl‐2; Kd=0.38 μM ; IC50=0.12 μM ). However, ABT‐737 and S1 had much weaker affinities to EEE‐Bcl‐2 (IC50=1.43 and >10 μM , respectively), compared with npBcl‐2 (IC50=0.011 and 0.74 μM , respectively). The allosteric effect on BH3 binding groove by Bcl‐2 phosphorylation in the loop region was illustrated for the first time. 相似文献