共查询到20条相似文献,搜索用时 0 毫秒
1.
Pfefferkorn JA Nugent R Gross RJ Greene M Mitchell MA Reding MT Funk LA Anderson R Wells PA Shelly JA Anstadt R Finzel BC Harris MS Kilkuskie RE Kopta LA Schwende FJ 《Bioorganic & medicinal chemistry letters》2005,15(11):2812-2818
A novel series of non-nucleoside HCV NS5B polymerase inhibitors was prepared from a (2Z)-2-benzoylamino-3-(4-phenoxy-phenyl)-acrylic acid template. Solution and solid phase analog synthesis focused on the northern region of the template combined with structure based design led to the discovery of several potent and orally bioavailable lead compounds. 相似文献
2.
Wiesner J Mitsch A Wissner P Krämer O Jomaa H Schlitzer M 《Bioorganic & medicinal chemistry letters》2002,12(19):2681-2683
In a previous report, we have described novel anti-malarial compounds based on a 2,5-diaminobenzophenone scaffold. Here, we have invesigated acryloyl derivatives carrying a biaryl structure consisting of a terminal aryl residue and a central 2-furyl ring. Several compounds were obtained in the series of para-substituted phenylfurylacryloyl derivatives that displayed improved anti-malarial activity in comparison to earlier described derivatives. From the structure-activity relationships it can be deduced that there has to be a lipophilic moiety in the para-position of the terminal phenyl residue. Furthermore, there are indications that, alternatively, activity may benefit from the presence of a polar moiety with hydrogen bond acceptor properties. 相似文献
3.
Pratt JK Donner P McDaniel KF Maring CJ Kati WM Mo H Middleton T Liu Y Ng T Xie Q Zhang R Montgomery D Molla A Kempf DJ Kohlbrenner W 《Bioorganic & medicinal chemistry letters》2005,15(6):1577-1582
N-1-Alkylamino and N-1-alkyloxy-4-hydroxyquinolon-3-yl benzothiadiazines were synthesized and evaluated as inhibitors of genotype 1 HCV polymerase. The N-1-alkyloxy derivatives were not potent inhibitors, however N-1-alkylamino derivatives displayed comparable potency to carbon analogs. Analogs with aliphatic substituents were significantly more potent than those with benzylic substituents against genotype 1a polymerase. The most potent inhibitors contained small alkyl or carbocyclic substituents and exhibited IC50's of 50-100 and 200-400 nM against genotype 1b and 1a HCV polymerase, respectively. 相似文献
4.
Light and elevated incubation temperature were found to be involved in the ability of four nitrofurans to cause the hereditary
bleaching effect inEuglena gracilis. The enzyme activation by S9 mix also played a significant role in the case of 3-(5-nitro-2-furyl)acrylic acid. When using
the combination of the above factors the most pronounced hereditary bleaching was reached. 相似文献
5.
The effect of 18 newly synthesized esters and amides of 3-(5-nitro-2-furyl)acrylic acid on bacteria (Escherichia coli, Staphylococcus aureus), yeasts (Saccharomyces cerevisiae, Candida albicans), molds (Aspergillus niger, Penicillium cyclopium, Rhizopus oryzae) and algae (Chlorella pyrenoidosa, Euglena gracilis, Scenedesmus obliquus) was investigated. The MIC values revealed antimycotic, antialgal and antibacterial activity of the studied derivates. The
antimycotic activity was found to decrease with increasing the length of the alkyl chain of esters and after introduction
of amino nitrogen into the furylethylene backbone. The inhibitory effect on growth is caused by blocking bioenergetic processes,
glycolysis in particular. 相似文献
6.
Robert T. Hendricks Jay B. Fell James F. Blake John P. Fischer John E. Robinson Stacey R. Spencer Peter J. Stengel April L. Bernacki Vincent J.P. Leveque Sophie Le Pogam Sonal Rajyaguru Isabel Najera John A. Josey Jason R. Harris Steven Swallow 《Bioorganic & medicinal chemistry letters》2009,19(13):3637-3641
The importance of internal hydrogen bonding in a series of benzothiadiazine and 1,4-benzothiazine NS5b inhibitors has been explored. Computational analysis has been used to compare the protonated vs. anionic forms of each series and we demonstrate that activity against HCV NS5b polymerase is best explained using the anionic forms. The syntheses and structure–activity relationships for a variety of new analogs are also discussed. 相似文献
7.
Chan L Das SK Reddy TJ Poisson C Proulx M Pereira O Courchesne M Roy C Wang W Siddiqui A Yannopoulos CG Nguyen-Ba N Labrecque D Bethell R Hamel M Courtemanche-Asselin P L'Heureux L David M Nicolas O Brunette S Bilimoria D Bédard J 《Bioorganic & medicinal chemistry letters》2004,14(3):793-796
The discovery of a novel class of HCV NS5B polymerase inhibitors, 3-arylsulfonylamino-5-phenyl-thiophene-2-carboxylic acids is described. SAR studies have yielded several potent inhibitors of HCV polymerase as well as of HCV subgenomic RNA replication in Huh-7 cells. 相似文献
8.
Kumar DV Rai R Brameld KA Riggs J Somoza JR Rajagopalan R Janc JW Xia YM Ton TL Hu H Lehoux I Ho JD Young WB Hart B Green MJ 《Bioorganic & medicinal chemistry letters》2012,22(1):300-304
The discovery and optimization of a novel class of quinolone small-molecules that inhibit NS5B polymerase, a key enzyme of the HCV viral life-cycle, is described. Our research led to the replacement of a hydrolytically labile ester functionality with bio-isosteric heterocycles. An X-ray crystal structure of a key analog bound to NS5B facilitated the optimization of this series of compounds to afford increased activity against the target enzyme and in the cell-based replicon assay system. 相似文献
9.
Wiesner J Mitsch A Jomaa H Schlitzer M 《Bioorganic & medicinal chemistry letters》2003,13(13):2159-2161
In a previous report, we have provided evidence that novel anti-malarial compounds based on 2,5-diaminobenzophenone farnesyltransferase inhibitors might benefit from the presence of a polar moiety at the para position of the terminal phenyl of the arylfurylacryloyl partial structure. Here, we demonstrate that different moieties with hydrogen bond acceptor properties lead to equipotent or even improved anti-malarial activity in comparison to the nitro group described before. 相似文献
10.
Wiesner J Fucik K Kettler K Sakowski J Ortmann R Jomaa H Schlitzer M 《Bioorganic & medicinal chemistry letters》2003,13(9):1539-1541
We have demonstrated that the p-trifluoromethylphenylpropionylamino residue at the 2-position of the core structure leads to an active benzophenone-type anti-malarial agent. The attempt to improve water solubility by introduction of an amino group into the alpha-position of the arylpropionyl residue resulted in decreased activity. 相似文献
11.
Krueger AC Madigan DL Jiang WW Kati WM Liu D Liu Y Maring CJ Masse S McDaniel KF Middleton T Mo H Molla A Montgomery D Pratt JK Rockway TW Zhang R Kempf DJ 《Bioorganic & medicinal chemistry letters》2006,16(13):3367-3370
Substituted N-alkyl-4-hydroxyquinolon-3-yl-benzothiadiazine sulfamides were investigated as inhibitors of genotype 1 HCV polymerase. Structure-activity relationship patterns for this class of compounds are discussed. 相似文献
12.
Javier de Vicente Robert T. Hendricks David B. Smith Jay B. Fell John Fischer Stacey R. Spencer Peter J. Stengel Peter Mohr John E. Robinson James F. Blake Ramona K. Hilgenkamp Calvin Yee Junping Zhao Todd R. Elworthy Jahari Tracy Elbert Chin Jim Li Al Lui Beihan Wang Connie Oshiro Tatyana Voronin 《Bioorganic & medicinal chemistry letters》2009,19(19):5648-5651
Benzothiazine-substituted tetramic acids were discovered as highly potent non-nucleoside inhibitors of HCV NS5B polymerase. X-ray crystallography studies confirmed the binding mode of these inhibitors with HCV NS5B polymerase. Rational optimization of time dependent inactivation of CYP 3A4 and clearance was accomplished by incorporation of electron-withdrawing groups to the benzothiazine core. 相似文献
13.
Hepatitis C virus (HCV) NS5A binds RNA-dependent RNA polymerase (RdRP) NS5B and modulates RNA-dependent RNA polymerase activity. 总被引:18,自引:0,他引:18
Yukihiro Shirota Hong Luo Weiping Qin Shuichi Kaneko Tatsuya Yamashita Kenichi Kobayashi Seishi Murakami 《The Journal of biological chemistry》2002,277(13):11149-11155
Hepatitis C virus (HCV) NS5B is RNA-dependent RNA polymerase (RdRP), the essential catalytic enzyme for HCV replication. Recently, NS5A has been reported to be important for the establishment of HCV replication in vitro by the adaptive mutations, although its role in viral replication remains uncertain. Here we report that purified bacterial recombinant NS5A and NS5B directly interact with each other in vitro, detected by glutathione S-transferase (GST) pull-down assay. Furthermore, complex formation of these proteins transiently coexpressed in mammalian cells was detected by coprecipitation. Using terminally and internally truncated NS5A, two discontinuous regions of NS5A (amino acids 105-162 and 277-334) outside of the adaptive mutations were identified to be independently essential for the binding both in vivo and in vitro (Yamashita, T., Kaneko, S., Shirota, Y., Qin, W., Nomura, T., Kobayashi, K., and Mkyrakami, S. (1998) J. Biol. Chem. 273, 15479-15486). We previously examined the effect of His-NS5A on RdRP activity of the soluble recombinant NS5Bt in vitro (see Yamashita et al. above). Wild NS5A weakly stimulated at first (when less than 0.1 molar ratio to NS5B) and then inhibited the NS5Bt RdRP activity in a dose-dependent manner. The internal deletion mutants defective in NS5B binding exhibited no inhibitory effect, indicating that the NS5B binding is necessary for the inhibition. Taken together, our results support the idea that NS5A modulates HCV replication as a component of replication complex. 相似文献
14.
Kettler K Sakowski J Silber K Sattler I Klebe G Schlitzer M 《Bioorganic & medicinal chemistry》2003,11(7):1521-1530
We have designed the nitrophenylfurylacryl-substituted benzophenone 4f as a non-thiol farnesyltransferase inhibitor utilizing a novel aryl binding site of farnesyltransferase. Variation of the 2-acylamino substituent at the benzophenone core structure of our initial lead 4f yielded several non-thiol farnesyltransferase inhibitors with improved activity. These compounds display activity in the low nanomolar range. 相似文献
15.
Frank Ruebsam Chinh V. Tran Lian-Sheng Li Sun Hee Kim Alan X. Xiang Yuefen Zhou Julie K. Blazel Zhongxiang Sun Peter S. Dragovich Jingjing Zhao Helen M. McGuire Douglas E. Murphy Martin T. Tran Nebojsa Stankovic David A. Ellis Alberto Gobbi Richard E. Showalter Stephen E. Webber Amit M. Shah Mei Tsan Leo Kirkovsky 《Bioorganic & medicinal chemistry letters》2009,19(2):451-458
5,6-Dihydro-1H-pyridin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Among these, compound 4ad displayed potent inhibitory activities in biochemical and replicon assays (IC50 (1b) < 10 nM; IC50 (1a) < 25 nM, EC50 (1b) = 16 nM), good in vitro DMPK properties, as well as moderate oral bioavailability in monkeys (F = 24%). 相似文献
16.
Donner PL Xie Q Pratt JK Maring CJ Kati W Jiang W Liu Y Koev G Masse S Montgomery D Molla A Kempf DJ 《Bioorganic & medicinal chemistry letters》2008,18(8):2735-2738
In our program to discover non-nucleoside, small molecule inhibitors of genotype 1 HCV polymerase, we investigated a series of promising analogs based on a benzothiadiazine screening hit that contains an ABCD ring system. After demonstrating that a methylsulfonylamino D-ring substituent increased the enzyme potency into the low nanomolar range, we explored a minimum core required for activity by truncating to a three-ring system. Described herein are the syntheses and structure-activity relationship of a set of inhibitors lacking the A-ring of an ABCD ring system. We observed that small aromatic rings and alkenyl groups appended to the 5-position of the B-ring were optimal, resulting in inhibitors with low nanomolar potencies. 相似文献
17.
Chan L Pereira O Reddy TJ Das SK Poisson C Courchesne M Proulx M Siddiqui A Yannopoulos CG Nguyen-Ba N Roy C Nasturica D Moinet C Bethell R Hamel M L'Heureux L David M Nicolas O Courtemanche-Asselin P Brunette S Bilimoria D Bédard J 《Bioorganic & medicinal chemistry letters》2004,14(3):797-800
Further SAR studies on the thiophene-2-carboxylic acids are reported. These studies led to the identification of a series of tertiary amides that show inhibition of both HCV NS5B polymerase in vitro and HCV subgenomic RNA replication in Huh-7 cells. Structural insights about the bioactive conformation of this class of molecules were deduced from a combination of modeling and transferred NOE (trNOE) studies. 相似文献
18.
《Bioorganic & medicinal chemistry letters》2020,30(7):126986
Our HCV research program investigated novel 2′-dihalogenated nucleoside HCV polymerase inhibitors and identified compound 1, a 5′-phosphoramidate prodrug of 2′-deoxy-2′-α-bromo-β-chloro uridine. Although 1 had a favorable in vitro activity profile in HCV replicons, oral dosing in dog resulted in low levels of the active 5′-triphosphate (TP) in liver. Metabolism studies using human hepatocytes provided a simple assay for screening alternative phosphoramidate prodrug analogs. Compounds that produced high TP concentrations in hepatocytes were tested in dog liver biopsy studies. This method identified 2-aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrug 14, which provided 100-fold higher TP concentrations in dog liver in comparison to 1 (4 and 24 h after 5 mg/kg oral dose). 相似文献
19.
Krueger AC Madigan DL Green BE Hutchinson DK Jiang WW Kati WM Liu Y Maring CJ Masse SV McDaniel KF Middleton TR Mo H Molla A Montgomery DA Ng TI Kempf DJ 《Bioorganic & medicinal chemistry letters》2007,17(8):2289-2292
Substituted 1-hydroxy-4,4-dialkyl-3-oxo-3,4-dihydronaphthalene benzothiadiazine derivatives were investigated as inhibitors of genotype 1 HCV polymerase. Structure-activity relationship patterns for this class of compounds are discussed. It was found that the saturated alkane dialkyl units provided the most active analogs. 相似文献
20.
Wiesner J Kettler K Sakowski J Ortmann R Jomaa H Schlitzer M 《Bioorganic & medicinal chemistry letters》2003,13(3):361-363
We have developed the [5-(4-nitrophenyl)-2-furyl]acrylic acid substituted benzophenone 4g as a novel lead for anti-malarial agents. Here, we demonstrated that the acyl residue at the 2-amino group of the benzophenone core structure has to be a phenylacetic acid substructure substituted in its para-position with methyl or other substituents of similar size. The trifluoromethyl substituted derivative displayed an IC(50) of 47 nM against the multi-drug resistant Plasmodium falciparum strain Dd2. 相似文献