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1.
Jong Yeon Hwang Hee-Young Kim Dong-Sik Park Jihyun Choi Sung Min Baek Keumhyun Kim Soohyun Kim Sikwang Seong Inhee Choi Hong-gun Lee Marc Peter Windisch Jinhwa Lee 《Bioorganic & medicinal chemistry letters》2013,23(23):6467-6473
In this report we describe the identification of novel pyrazole analogs as potent hepatitis C virus (HCV) entry inhibitor. The pyrazoles were identified by our phenotypic high-throughput screening using infectious HCV. A series of pyrazole derivatives was synthesized and evaluated for inhibitory activity against HCV in the infectious cell culture system. Through evaluation of selected compounds we observed that the pyrazoles did not interfere with HCV RNA replication but with viral entry as shown by experiments with HCV replicons and HCV pseudo particles, respectively. 相似文献
2.
Inorganic pyrophosphate (PPi) is a product of the polymerization reaction catalyzed by DNA- and RNA-polymerases. We have synthesized a number of novel non-hydrolysable PPi analogues, some of them have demonstrated inhibition of polymerization reaction catalyzed by hepatitis C virus RNA-dependent RNA-polymerase (NS5B). A new pharmacophore has been developed based on non-hydrolysable methylene-diphosphonate backbone. Structure-activity relationship analysis of 12 bisphosphonates is presented and structural features crucial for the ability of molecule to inhibit NS5B polymerase activity are ascertained. 相似文献
3.
Iou-Jiun Kang Li-Wen Wang Sheng-Ju Hsu Chung-Chi Lee Yen-Chun Lee Yen-Shian Wu Andrew Yueh Jing-Chyi Wang Tsu-An Hsu Yu-Sheng Chao Jyh-Haur Chern 《Bioorganic & medicinal chemistry letters》2009,19(21):6063-6068
A novel class of arylthiourea HCV inhibitors bearing various functionalities, such as cyclic urea, cyclic thiourea, urea, and thiourea, on the alkyl linker were designed and synthesized. Herein we report the synthesis and structure–activity relationships (SARs) of this novel class of arylthiourea derivatives that showed potent inhibitory activities against HCV in the cell-based subgenomic HCV replicon assay. Among compounds tested, the new carbazole derivative 64, which has an eight-carbon linkage between the phenyl and carbazole rings and a tolyl group at the N-9 position of carbazole, was found to possess strong anti-HCV activity (EC50 = 0.031 μM), lower cytotoxicity (CC50 >50 μM), and higher selectivity index (SI >1612) compared to its derivatives. 相似文献
4.
X. Christopher Sheng Hyung-Jung Pyun Kleem Chaudhary Jianying Wang Edward Doerffler Melissa Fleury Darren McMurtrie Xiaowu Chen William E. Delaney Choung U. Kim 《Bioorganic & medicinal chemistry letters》2009,19(13):3453-3457
A novel class of phosphonate derivatives was designed to mimic the interaction of product-like carboxylate based inhibitors of HCV NS3 protease. A phosphonic acid (compound 2) was demonstrated to be a potent HCV NS3 protease inhibitor, and a potential candidate for treating HCV infection. The syntheses and preliminary biological evaluation of this phosphonate class of inhibitor are described. 相似文献
5.
Ortqvist P Peterson SD Kerblom E Gossas T Sabnis YA Fransson R Lindeberg G Helena Danielson U Karlén A Sandström A 《Bioorganic & medicinal chemistry》2007,15(3):1448-1474
Molecular modeling and inhibitory potencies of tetrapeptide protease inhibitors of HCV NS3 proposed phenylglycine as a new promising P2 residue. The results suggest that phenylglycine might be capable of interacting with the NS3 (protease-helicase/NTPase) in ways not possible for the common P2 proline-based inhibitors. Thus, a series of tripeptides, both linear and macrocyclic, based on p-hydroxy-phenylglycine in the P2 position were prepared and their inhibitory effect determined. When the p-hydroxy group was replaced by methoxy, isoquinolin-, or quinolinyloxy functions, inhibitors with improved potencies were obtained. The P2 phenylglycine-based inhibitors were further optimized by C-terminal extension to acyl sulfonamides and by P1-P3 cyclization, which gave products with inhibition constants in the nanomolar range ( approximately 75nM). 相似文献
6.
Jiaying Sun Shaoxi Cai Hu Mei Jian Li Ning Yan Yuanqiang Wang 《Journal of molecular modeling》2010,16(12):1809-1818
Surflex-Dock was applied to study interactions between 30 thiourea analogs and neuraminidase (NA). The docking results showed
that hydrogen bonding and electrostatic interactions were highly correlated with the activities of neuraminidase inhibitors
(NIs), followed by hydrophobic and steric factors. Moreover, there was a strong correlation between the predicted binding
affinity (total score) and experimental pIC50 (correlation coefficient r = 0.870; P < 0.0001). A three dimensional holographic vector of atomic interaction field (3D-HoVAIF) was employed to construct a QSAR
model. The r
2, q
2 and r
2
test values of the optimal QSAR model were 0.849, 0.724 and 0.689, respectively. From the QSAR model, it could be seen that electrostatic,
hydrophobic and steric interactions were closely related to inhibitory activity, which was consistent with the docking results.
Based on the docking and QSAR results, five new compounds with high predicted activities were designed. 相似文献
7.
《Bioorganic & medicinal chemistry letters》2014,24(2):609-612
The bacterial natural product UK-1 and several structural analogs inhibit replication of the hepatitis C virus in the replicon assay, with IC50 values as low as 0.50 μM. The NS3 helicase has been identified as a possible target of inhibition for several of these compounds, while the remaining inhibitors act via an undetermined mechanism. Gel shift assays suggest that helicase inhibition is a direct result of inhibitor–enzyme binding as opposed to direct RNA binding, and the ATPase activity of NS3 is not affected. The syntheses and biological results are presented herein. 相似文献
8.
Development of a GB virus B marmoset model and its validation with a novel series of hepatitis C virus NS3 protease inhibitors 总被引:6,自引:0,他引:6
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GB virus B (GBV-B), a flavivirus closely related to HCV, has previously been shown to infect and replicate to high titers in tamarins (Saguinus sp.). This study describes the use of GBV-B infection and replication in the common marmoset (Callithrix jacchus) for the successful development and validation of a surrogate animal model for hepatitis C virus (HCV). Infection of marmosets with GBV-B produced a viremia that peaked at 10(8) to 10(9) genome copies/ml for a period of 40 to 60 days followed by viral clearance at 60 to 80 days postinfection. Passage of the initial tamarin-derived GBV-B in marmosets produced an infectious stock that gave a more reproducible and consistent infection in the marmoset. Titration of the virus stocks in vivo indicated that they contained 1 infectious unit for every 1,000 genome copies. Cultures of primary marmoset hepatocytes were also successfully infected with GBV-B, with high levels of virus detected in supernatants and cells for up to 14 days postinfection. Treatment of GBV-B-infected hepatocyte cultures with a novel class of HCV protease inhibitor (pyrrolidine 5,5 trans-lactams) reduced viral levels by more than 2 logs. Treatment of GBV-B-infected marmosets with one such inhibitor resulted in a 3-log drop in serum viral titer over 4 days of therapy. These studies provide the first demonstration of the in vivo efficacy of a small-molecule inhibitor for HCV in an animal model and illustrate the utility of GBV-B as a surrogate animal model system for HCV. 相似文献
9.
Harshani R. Lawrence Aslamuzzaman Kazi Yunting Luo Robert Kendig Yiyu Ge Sanjula Jain Kenyon Daniel Daniel Santiago Wayne C. Guida Saïd M. Sebti 《Bioorganic & medicinal chemistry》2010,18(15):5576-5592
Screening of the NCI Diversity Set-1 identified PI-083 (NSC-45382) a proteasome inhibitor selective for cancer over normal cells. Focused libraries of novel compounds based on PI-083 chloronaphthoquinone and sulfonamide moieties were synthesized to gain a better understanding of the structure–activity relationship responsible for chymotrypsin-like proteasome inhibitory activity. This led to the demonstration that the chloronaphthoquinone and the sulfonamide moieties are critical for inhibitory activity. The pyridyl group in PI-083 can be replaced with other heterocyclic groups without significant loss of activity. Molecular modeling studies were also performed to explore the detailed interactions of PI-083 and its derivatives with the β5 and β6 subunits of the 20S proteasome. The refined model showed an H-bond interaction between the Asp-114 and the sulfonamide moiety of the PI-083 in the β6 subunit. 相似文献
10.
Gudmundsson KS Daluge SM Condreay LD Johnson LC 《Nucleosides, nucleotides & nucleic acids》2002,21(11-12):891-901
Synthesis and antiviral activity of several new 8-substituted carbocyclic analogs of D-2',3'-dideoxyadenosine are described. The new 8-substituted analogs were synthesized via lithiation of carbocyclic 2',3'-dideoxyadenosine followed by quenching with electrophiles. This methodology allows for a divergent synthesis of a variety of 8-substituted analogs from carbocyclic 2',3'-dideoxyadenosine in high yields. 8-Methyl and 8-halogenated carbocyclic 2',3'-dideoxyadenosine analogs showed 6-25 fold more activity against hepatitis B virus than the unsubstituted carbocyclic D-2',3'-dideoxyadenosine. 相似文献
11.
Randolph JT Huang PP Flosi WJ DeGoey D Klein LL Yeung CM Flentge C Sun M Zhao C Dekhtyar T Mo H Colletti L Kati W Marsh KC Molla A Kempf DJ 《Bioorganic & medicinal chemistry》2006,14(12):4035-4046
As a continuation of the recently communicated discovery of oximinoarylsulfonamides as potent inhibitors of HIV-1 aspartyl protease, compounds bearing pyridylmethyl substituents at P3 were designed and synthesized. Potent analogs in this series provided low single-digit nanomolar EC50 values against both wild-type HIV and resistant mutant virus (A17), attenuated some 3- to 12-fold in the presence of 50% human serum. Pharmacokinetic results for compounds in this series showed good to excellent exposure when co-administered orally with an equal amount of ritonavir (5mg/kg each) in the rat, with average AUC >8 microg h/mL. Similar dosing in dog resulted in significantly lower plasma levels (average AUC <2 microg h/mL). The 3-pyridylmethyl analog 30 gave the best overall exposure (rat AUC=7.1 microg h/mL and dog AUC=4.9 microg h/mL), however, this compound was found to be a potent inhibitor of cytochrome P450 3A (Ki=2.4 nM). 相似文献
12.
A three series of thioureas, monothiourea type I (4a–g), 1,4-bisthiourea type II (5a–h) and 1,3-bisthiourea type III (6a–h) were synthesized. Their aromatase inhibitory activities have been evaluated. Interestingly, eight thiourea derivatives (4e, 5f–h, 6d, 6f–h) exhibited the aromatase inhibitory activities with IC50 range of 0.6–10.2 μM. The meta-bisthiourea bearing 4-NO2 group (6f) and 3,5-diCF3 groups (6h) were shown to be the most potent compounds with sub-micromolar IC50 values of 0.8 and 0.6 μM, respectively. Molecular docking also revealed that one of the thiourea moieties of these two compounds could mimic steroidal backbone of the natural androstenedione (ASD) via hydrophobic interactions with enzyme residues (Val370, Leu477, Thr310, and Phe221 for 6f, Val370, Leu477, Ser478, and Ile133 for 6h). This is the first time that the bisthioureas have been reported for their potential to be developed as aromatase inhibitors, in which the 4-NO2 and 3,5-diCF3 analogs have been highlighted as promising candidates. 相似文献
13.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(2):302-310
A series of novel L-isoserine derivatives were synthesised and evaluated for their ability to inhibit aminopeptidase N (APN)/CD13. In our preliminary biological results, some of these compounds possessed a potent inhibitory activity against the APN. Within this series, compound 14b not only showed similar enzyme inhibition (IC50 of 12.2?μM) compared with the positive control bestatin (half maximal inhibitory concentration (IC50) of 7.3?μM), but also had a potent antiproliferative activity against human cancer cell lines cells. 相似文献
14.
François Bilodeau Murray D. Bailey Punit K. Bhardwaj Josée Bordeleau Pat Forgione Michel Garneau Elise Ghiro Vida Gorys Ted Halmos Eric S. Jolicoeur Mélissa Leblanc Christopher T. Lemke Julie Naud Jeff O’Meara Peter W. White Montse Llinàs-Brunet 《Bioorganic & medicinal chemistry letters》2013,23(14):4267-4271
In this report we describe the synthesis and evaluation of diverse 4-arylproline analogs as HCV NS3 protease inhibitors. Introduction of this novel P2 moiety opened up new SAR and, in combination with a synthetic approach providing a versatile handle, allowed for efficient exploitation of this novel series of NS3 protease inhibitors. Multiple structural modifications of the aryl group at the 4-proline, guided by structural analysis, led to the identification of analogs which were very potent in both enzymatic and cell based assays. The impact of this systematic SAR on different drug properties is reported. 相似文献
15.
Yang K Fen J Fang H Zhang L Gong J Xu W 《Journal of enzyme inhibition and medicinal chemistry》2012,27(2):302-310
A series of novel L-isoserine derivatives were synthesised and evaluated for their ability to inhibit aminopeptidase N (APN)/CD13. In our preliminary biological results, some of these compounds possessed a potent inhibitory activity against the APN. Within this series, compound 14b not only showed similar enzyme inhibition (IC?? of 12.2 μM) compared with the positive control bestatin (half maximal inhibitory concentration (IC??) of 7.3 μM), but also had a potent antiproliferative activity against human cancer cell lines cells. 相似文献
16.
Bera S Malik L Bhat B Carroll SS MacCoss M Olsen DB Tomassini JE Eldrup AB 《Bioorganic & medicinal chemistry letters》2003,13(24):4455-4458
A series of optically pure 1,3-dioxolane nucleoside mimics was synthesized by a synthetic route that allowed incorporation of a 5R-methyl substituent from commercially available starting materials. The pyrrolo[2,3-d]pyrimidine heterocycle was chosen as a substitute for the purine derivative. Coupling of the pyrrolo[2,3-d]pyrimidine and the dioxolane was performed under solid–liquid phase transfer conditions. The ability to inhibit HCV RNA replication was assessed in a cell based subgenomic replicon assay. None of the described compounds displayed significant anti-HCV activity. 相似文献
17.
Hiroshi Imagawa Masataka Oda Takayuki Takemoto Rieko Yamauchi Tomomi Yoshikawa Hirofumi Yamamoto Mugio Nishizawa Hironobu Takahashi Manabu Hashimoto Kenta Yabiku Masahiro Nagahama Jun Sakurai 《Bioorganic & medicinal chemistry letters》2010,20(13):3868-3871
A novel sphingomyelin inhibitor RY221B-a, which contains a bipyridyl moiety as a metal coordination site was designed based upon the mechanism of phosphate ester hydrolysis. RY221B-a was synthesized from N-Boc-sphingosine in three steps via selective etherification using stannyl acetal. Synthesized RY221B-a exhibited relatively-strong inhibitory activity against Bc-SMase (IC50 = 1.2 μM). 相似文献
18.
Aamer Saeed Gufran Saddique Pervaiz Ali Channar Fayaz Ali Larik Qamar Abbas Mubashir Hassan Hussain Raza Tanzeela Abdul Fattah Sung-Yum Seo 《Bioorganic & medicinal chemistry》2018,26(12):3707-3715
To seek the new medicinal potential of sulfadiazine drug, the free amino group of sulfadiazine was exploited to obtain acyl/aryl thioureas using simple and straightforward protocol. Acyl/aryl thioureas are well recognized bioactive pharmacophore containing moieties. A new series (4a–4j) of sulfadiazine derived acyl/aryl thioureas was synthesized and characterized through spectroscopic and elemental analysis. The synthesized derivatives 4a–4j were subjected to calf intestinal alkaline phosphatase (CIAP) activity. The derivative 4a–4j showed better inhibition potential compared to standard monopotassium phosphate (MKP). The compound 4c exhibited higher potential in the series with IC50 0.251?±?0.012?µM (standard KH2PO4 4.317?±?0.201?µM). Lineweaver-Burk plots revealed that most potent derivative 4c inhibition CIAP via mixed type pathway. Pharmacological investigations showed that synthesized compounds 4a–4j obey Lipinsk’s rule. ADMET parameters evaluation predicted that these molecule show significant lead like properties with minimum possible toxicity and can serve as templates in drug designing. The synthetic compounds show none mutagenic and irritant behavior. Molecular docking analysis showed that compound 4c interacts with Asp273, His317 and Arg166 amino acid residues. 相似文献
19.
Giovanna Delogu Gianni Podda Marcella Corda Maria Benedetta Fadda Antonella Fais Benedetta Era 《Bioorganic & medicinal chemistry letters》2010,20(20):6138-6140
A series of novel bis-salicylaldehydes were synthesised and evaluated as tyrosinase inhibitors using a tyrosinase-dependent l-DOPA oxidation assay. The bis-salicylaldehydes exhibited greater inhibitory activity than salicylaldehyde. Our data suggests that these novel compounds may serve as a structural template for the design and development of novel tyrosinase inhibitors. 相似文献
20.
Z Xu J Choi T S Yen W Lu A Strohecker S Govindarajan D Chien M J Selby J Ou 《The EMBO journal》2001,20(14):3840-3848
Hepatitis C virus (HCV) is an important human pathogen that affects approximately 100 million people worldwide. Its RNA genome codes for a polyprotein, which is cleaved by viral and cellular proteases to produce at least 10 mature viral protein products. We report here the discovery of a novel HCV protein synthesized by ribosomal frameshift. This protein, which we named the F protein, is synthesized from the initiation codon of the polyprotein sequence followed by ribosomal frameshift into the -2/+1 reading frame. This ribosomal frameshift requires only codons 8-14 of the core protein-coding sequence, and the shift junction is located at or near codon 11. An F protein analog synthesized in vitro reacted with the sera of HCV patients but not with the sera of hepatitis B patients, indicating the expression of the F protein during natural HCV infection. This unexpected finding may open new avenues for the development of anti-HCV drugs. 相似文献