Abstract:
:The metal ion chelating β-N-hydroxy-γ-ketocarboxamide pharmacophore was integrated into a quinazolinone scaffold, leading to N-arylalkyl-3-hydroxy-4-oxo-3,4-dihydroquinazolin-2-carboxamide derivatives as hepatitis C virus (HCV) NS5B polymerase inhibitors. Lead optimization led to the identification of N-phenylpropyl carboxamide 9 k (IC(50) =8.8 μM). Compound 9 k possesses selectivity toward HCV1b replicon Ava.5 cells (EC(50) =17.5 μM) over parent Huh-7 cells (CC(50) =187.5 μM). Compound 9 k effects a mixed mode of NS5B inhibition, with NTP-competitive displacement properties. The interaction between 9 k and NS5B is stabilized by the presence of magnesium ions. Docking studies showed that the binding orientation of 9 k occupies the central portions of both magnesium-mediated and NTP-ribose-response binding sites within the active site region of NS5B. As a result, 3-hydroxy-4-oxo-3,4-dihydroquinazolin-2-carboxamide derivatives are disclosed herein as novel, mainly active site inhibitors of HCV NS5B polymerase.
journal_name
ChemMedChemjournal_title
ChemMedChemauthors
Deore RR,Chen GS,Chang PT,Chern TR,Lai SY,Chuang MH,Lin JH,Kung FL,Chen CS,Chiou CT,Chern JWdoi
10.1002/cmdc.201200058subject
Has Abstractpub_date
2012-05-01 00:00:00pages
850-60issue
5eissn
1860-7179issn
1860-7187journal_volume
7pub_type
杂志文章相关文献
ChemMedChem文献大全abstract::Nanoscale materials hold great promise in the therapeutic field. In particular, as carriers or vectors, they help bioactive molecules reach their primary targets. Furthermore, by themselves, certain nanomaterials-regarded as protective-can modulate particular metabolic pathways that are deregulated in pathological sit...
journal_title:ChemMedChem
pub_type: 杂志文章,评审
doi:10.1002/cmdc.201500233
更新日期:2016-01-19 00:00:00
abstract::Chemical biology approaches have a long history in the exploration of the G-protein-coupled receptor (GPCR) family, which represents the largest and most important group of targets for therapeutics. The analysis of the human genome revealed a significant number of new members with unknown physiological function which ...
journal_title:ChemMedChem
pub_type: 历史文章,杂志文章,评审
doi:10.1002/cmdc.200600134
更新日期:2006-08-01 00:00:00
abstract::The clinical use of N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED) has been hindered by its lack of bioavailability. N,N'-bis(2-boronic pinacol ester benzyl)ethylenediamine-N,N'-diacetic acid methyl, ethyl, and isopropyl esters 7 a-c, respectively, and their dimesylate salts 8 a-c, are double prodr...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201600197
更新日期:2016-08-05 00:00:00
abstract::Two acyclic cucurbit[n]uril (CB[n])-type molecular containers that differ in the length of the (CH2 )n linker (M2C2: n=2, M2C4: n=4) between their aromatic sidewalls and sulfonate solubilizing groups were prepared and studied. The inherent solubilities of M2C2 (68 mm) and M2C4 (196 mm) are higher than the analogue wit...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201600090
更新日期:2016-05-06 00:00:00
abstract::2-Azetidinones, commonly known as beta-lactams, are well-known heterocyclic compounds. Herein we described the synthesis and biological evaluation of a series of novel beta-lactams. In vitro inhibition assays against HDAC isoforms showed an interesting isoform-selectivity of these compounds towards HDAC6 and HDAC8. Th...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200900309
更新日期:2009-12-01 00:00:00
abstract::Histone deacetylases (HDACs) are promising drug targets for a variety of therapeutic applications. Herein we describe the design, synthesis, biological evaluation in cellular models of cancer, and preliminary drug metabolism and pharmacokinetic studies (DMPK) of a series of secondary and tertiary N-substituted 7-amino...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700449
更新日期:2017-12-19 00:00:00
abstract::Progesterone plays an important role in the female reproductive system. However, there is also evidence that gynecologic disorders/diseases such as uterine fibroids and endometriosis are progesterone-dependent. Steroidal and non-steroidal selective progesterone receptor modulators (SPRMs) have shown potential for the ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201800487
更新日期:2018-11-06 00:00:00
abstract::S100B contributes to cell proliferation by binding the C terminus of p53 and inhibiting its tumor suppressor function. The use of multiple computational approaches to screen fragment libraries targeting the human S100B-p53 interaction site is reported. This in silico screening led to the identification of 280 novel pr...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200900393
更新日期:2010-03-01 00:00:00
abstract::The histamine H1 G protein-coupled receptor (GPCR) plays an important role in allergy and inflammation. Existing drugs that address the H1 receptor differ in their chemical structure, pharmacology, and side effects. Light-controllable spatial and temporal activity regulation of photochromic H1 ligands may contribute t...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201800815
更新日期:2019-03-22 00:00:00
abstract::Prodrugs are effective tools in overcoming drawbacks typically associated with drug formulation and delivery. Those employing esterase-triggered functional groups are frequently utilized to mask polar carboxylic acids and phenols, increasing drug-like properties such as lipophilicity. Herein we detail a comprehensive ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201300255
更新日期:2013-10-01 00:00:00
abstract::Recently we reported on aryl-fluorosulfates as possible stable and effective electrophiles for the design of lysine covalent, cell permeable antagonists of protein-protein interactions (PPIs). Here we revisit the use of aryl-sulfonyl fluorides as Lys-targeting moieties, incorporating these electrophiles in XIAP (X-lin...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.202000355
更新日期:2020-11-18 00:00:00
abstract::A series of new substituted 7-phenyl-3H-pyrrolo[3,2-f]quinolin-9-ones were synthesized and evaluated for their antiproliferative activity. The most active derivatives showed high selectivity against human leukemia cell lines and potently inhibited their growth, with GI(50) values in the nanomolar range. The active com...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201000180
更新日期:2010-08-02 00:00:00
abstract::Protein-protein interactions (PPIs) control many cellular processes in cancer and tumour growth. Of significant interest is the role PPIs play in regulating apoptosis. The overexpression of the antiapoptosis regulating Bcl-2 family of proteins is commonly observed in several cancers, leading to resistance towards both...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201500488
更新日期:2016-04-19 00:00:00
abstract::The Eph-ephrin system, including the EphA2 receptor and the ephrinA1 ligand, plays a critical role in tumor and vascular functions during carcinogenesis. We previously identified (3α,5β)-3-hydroxycholan-24-oic acid (lithocholic acid) as an Eph-ephrin antagonist that is able to inhibit EphA2 receptor activation; it is ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200102
更新日期:2012-06-01 00:00:00
abstract::Uropathogenic E. coli (UPEC) employ the mannose-binding adhesin FimH to colonize the bladder epithelium during urinary tract infection (UTI). Previously reported FimH antagonists exhibit good potency and efficacy, but low bioavailability and a short half-life in vivo. In a rational design strategy, we obtained an X-ra...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201600006
更新日期:2016-02-17 00:00:00
abstract::Cellular chaperones that belong to the heat-shock protein 90 (Hsp90) family are a prerequisite for successful viral propagation for most viruses. The hepatitis C virus (HCV) uses Hsp90 for maturation, folding, and modification of viral proteins. Based on our previous discovery that marine alkaloid analogues with a 4,5...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201800724
更新日期:2019-02-05 00:00:00
abstract::A series of 1,3,3,4-tetrasubstituted pyrrolidine containing CCR5 receptor antagonists were designed, which were elaborated either by condensation of a lithium salt of 3-(N,N-dibenzyl)aminopropionic acid methyl ester with ethyl benzoformate or by Baylis-Hillman reaction of ethyl acrylate with ethyl benzoformate and sub...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200600182
更新日期:2007-02-01 00:00:00
abstract::There is an urgent clinical need for imaging of α-synuclein (αSyn) fibrils, the hallmark biomarker for Parkinson's disease, in neurodegenerative disorders. Despite immense efforts, promising tracer candidates for nuclear imaging of αSyn are rare. Diphenyl pyrazoles are known modulators of αSyn aggregation and thus bea...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201900689
更新日期:2020-03-05 00:00:00
abstract::A small library of 17 organoruthenium compounds with the general formula [RuII (fcl)(chel)(L)]n+ (in which fcl=face capping ligand, chel=chelating bidentate ligand, and L=monodentate ligand) were screened for inhibitory activity against cholinesterases and glutathione-S-transferases of human and animal origins. Compou...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201800432
更新日期:2018-10-22 00:00:00
abstract::Racemic 2-{[1-(chloromethyl)-5-nitro-3-{5-[2-(dimethylamino)ethoxy]indol-2-carbonyl}-1,2-dihydro-3H-benzo[e]indol-7-yl]sulfonyl}aminoethyl dihydrogen phosphate, a synthetic nitro derivative of the duocarmycins, is a hypoxia-selective prodrug active against radiation-resistant tumour cells at nontoxic doses in mice. An...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201100271
更新日期:2011-10-04 00:00:00
abstract::The spider polyamine toxins Joro spider toxin-3 (JSTX-3) and Nephila polyamine toxins-1 and -8 (NPTX-1 and NPTX-8) are isolated from the venom of the orb-weaver spider Nephila clavata (Joro spider). They share a high degree of structural resemblance, their aromatic head groups being the only difference, and were recen...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201402278
更新日期:2014-12-01 00:00:00
abstract::N-Acylethanolamine acid amidase (NAAA) is a cysteine hydrolase that catalyzes the hydrolysis of endogenous lipid mediators such as palmitoylethanolamide (PEA). PEA has been shown to exert anti-inflammatory and antinociceptive effects in animals by engaging peroxisome proliferator-activated receptor α (PPAR-α). Thus, p...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201300546
更新日期:2014-07-01 00:00:00
abstract::HIV protease is a promising drug target for AIDS therapy, and several potent HIV-1 protease inhibitors have been reported to date. Although existing inhibitors exhibit high selectivity, they have also been associated with severe side effects and the possible emergence of therapeutic resistance. As HIV protease cleaves...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200271
更新日期:2012-09-01 00:00:00
abstract::In an attempt to develop potent anticancer agents, a series of 2-anilinonicotinyl-linked acrylamide conjugates were designed, synthesized, and evaluated for cytotoxic activity against various human cancer cell lines, anti-tubulin activity and cell-cycle effects. Among the series, compounds 6 d [(E)-N-(6-fluorobenzo[d]...
journal_title:ChemMedChem
pub_type: 杂志文章,收录出版
doi:10.1002/cmdc.201400036
更新日期:2014-03-28 00:00:00
abstract::Abnormally high corticosteroid levels are responsible for the onset of serious hormone-related diseases, and the inhibition of their biosynthesis by targeting cytochrome P450 (CYP) isoforms CYP11B1 and CYP11B2 has emerged as a promising strategy to restore healthy physiological levels of corticosteroids. With the aim ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201600078
更新日期:2016-08-19 00:00:00
abstract::In the present review the crucial role of the guanidinium functional group in facilitating the transport of dendritic polymers through liposomal and cell membranes is discussed, along with other structural features of guanidinylated dendritic polymers that fine-tune their transport properties, and even determine their...
journal_title:ChemMedChem
pub_type: 杂志文章,评审
doi:10.1002/cmdc.200800190
更新日期:2008-11-01 00:00:00
abstract::Based on the crystal structures of human alpha-GalCer-CD1d and iNKT-alpha-GalCer-CD1d complexes, nonglycosidic analogues of alpha-GalCer were synthesized. They activate iNKT cells resulting in dendritic cell maturation and the priming of antigen-specific T and B cells. Therefore, they are attractive adjuvants in vacci...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200800354
更新日期:2009-02-01 00:00:00
abstract::Greater than the sum of its parts: Artemisinins are currently in phase I-II clinical trials against breast, colorectal and non-small-cell lung cancers. In an attempt to offer increased specificity, a series of hybrid artemisinin-polypyrrole minor groove binder conjugates are described. DNA binding/modelling studies an...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200536
更新日期:2013-05-01 00:00:00
abstract::Bromodomains (BRDs) are small protein domains found in a variety of proteins that recognize and bind to acetylated histone tails. This binding affects chromatin structure and facilitates the localisation of transcriptional complexes to specific genes, thereby regulating epigenetically controlled processes including ge...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201300259
更新日期:2014-03-01 00:00:00
abstract::Here we report the synthesis of a number of compounds structurally related to arginine methyltransferase inhibitor 1 (AMI-1). The structural alterations that we made included: 1) the substitution of the sulfonic groups with the bioisosteric carboxylic groups; 2) the replacement of the ureidic function with a bis-amidi...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200900459
更新日期:2010-03-01 00:00:00