Abstract:
:(±)-6-Alkyl-2,4-diaminopyrimidine-based inhibitors of bacterial dihydrofolate reductase (DHFR) have been prepared and evaluated for biological potency against Bacillus anthracis and Staphylococcus aureus. Biological studies revealed attenuated activity relative to earlier structures lacking substitution at C6 of the diaminopyrimidine moiety, though minimum inhibitory concentration (MIC) values are in the 0.125-8 μg mL(-1) range for both organisms. This effect was rationalized from three- dimensional X-ray structure studies that indicate the presence of a side pocket containing two water molecules adjacent to the main binding pocket. Because of the hydrophobic nature of the substitutions at C6, the main interactions are with protein residues Leu 20 and Leu 28. These interactions lead to a minor conformational change in the protein, which opens the pocket containing these water molecules such that it becomes continuous with the main binding pocket. These water molecules are reported to play a critical role in the catalytic reaction, highlighting a new area for inhibitor expansion within the limited architectural variation at the catalytic site of bacterial DHFR.
journal_name
ChemMedChemjournal_title
ChemMedChemauthors
Nammalwar B,Bourne CR,Bunce RA,Wakeham N,Bourne PC,Ramnarayan K,Mylvaganam S,Berlin KD,Barrow EW,Barrow WWdoi
10.1002/cmdc.201200291subject
Has Abstractpub_date
2012-11-01 00:00:00pages
1974-82issue
11eissn
1860-7179issn
1860-7187journal_volume
7pub_type
杂志文章相关文献
ChemMedChem文献大全abstract::A series of four stable synthetic bacteriochlorins was tested in vitro in HeLa cells for their potential in photodynamic therapy (PDT). The parent bacteriochlorin (BC), dicyano derivative (NC)(2)BC and corresponding zinc chelate (NC)(2)BC-Zn and palladium chelate (NC)(2)BC-Pd were studied. Direct dilution of a solutio...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200351
更新日期:2012-12-01 00:00:00
abstract::A strategy that combines virtual screening and structure-guided selection of fragments was used to identify three unexplored classes of human DHODH inhibitor compounds: 4-hydroxycoumarins, fenamic acids, and N-(alkylcarbonyl)anthranilic acids. Structure-guided selection of fragments targeting the inner subsite of the ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200900454
更新日期:2010-04-06 00:00:00
abstract::Structural preorganization to fix bioactive conformations at protein binding sites is a popular strategy to enhance binding affinity during late-stage optimization. The rationale for this enhancement relates to entropic advantages assigned to rigidified versus flexible ligands. We analyzed a narrow series of peptidomi...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201500531
更新日期:2016-02-04 00:00:00
abstract::Over the years, a number of dimensionality reduction techniques have been proposed and used in chemoinformatics to perform nonlinear mappings. In this study, four representatives of nonlinear dimensionality reduction methods related to two different families were analyzed: distance-based approaches (Isomap and Diffusi...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201400027
更新日期:2014-05-01 00:00:00
abstract::In the present work, a series of small molecules were designed and synthesized based on structural optimization. A significant improvement in the enzyme inhibitory activity of these compounds was discovered. Moreover, the tested compounds have moderate preference for class I HDACs over HDAC6, as demonstrated by enzyme...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201300297
更新日期:2014-03-01 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::Src homology 2 (SH2)-domain-mediated interactions with phosphotyrosine (pY)-containing ligands are critical for the regulation of SHP-1 phosphatase activity. Peptides based on a binding site from receptor tyrosine kinase Ros (EGLN-pY2267-MVL, 1) have recently been shown to bind to the SHP-1 N-terminal SH2 domain (N-SH...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200600037
更新日期:2006-08-01 00:00:00
abstract::Blocking the 2-C-methyl-d-erythrithol-4-phosphate pathway for isoprenoid biosynthesis offers new ways to inhibit the growth of Plasmodium spp. Fosmidomycin [(3-(N-hydroxyformamido)propyl)phosphonic acid, 1] and its acetyl homologue FR-900098 [(3-(N-hydroxyacetamido)propyl)phosphonic acid, 2] potently inhibit 1-deoxy-d...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201600249
更新日期:2016-09-20 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::A series of sulfocoumarin-, coumarin-, and 4-sulfamoylphenyl-bearing indazole-3-carboxamide hybrids were synthesized and investigated as inhibitors of the human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms I and II (cytosolic isozymes), as well as hCA IX and XII (transmembrane, tumor-associated enzymes). Compounds 6 ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700446
更新日期:2017-10-09 00:00:00
abstract::The potassium channel openers flupirtine and retigabine have proven to be valuable analgesics or antiepileptics. Their recent withdrawal due to occasional hepatotoxicity and tissue discoloration, respectively, leaves a therapeutic niche unfilled. Metabolic oxidation of both drugs gives rise to the formation of electro...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201900112
更新日期:2019-05-06 00:00:00
abstract::For (64) Cu radiolabeling of biomolecules to be used as in vivo positron emission tomography (PET) imaging agents, various chelators are commonly applied. It has not yet been determined which of the most potent chelators--NODA-GA ((1,4,7-triazacyclononane-4,7-diyl)diacetic acid-1-glutaric acid), CB-TE2A (2,2'-(1,4,8,1...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201500132
更新日期:2015-07-01 00:00:00
abstract::Aberrant WNT pathway activation, leading to nuclear accumulation of β-catenin, is a key oncogenic driver event. Mutations in the tumor suppressor gene APC lead to impaired proteasomal degradation of β-catenin and subsequent nuclear translocation. Restoring cellular degradation of β-catenin represents a potential thera...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.202000839
更新日期:2020-12-04 00:00:00
abstract::Targeted structural modifications have led to a novel type of buprenorphine-derived opioid receptor ligand displaying an improved selectivity profile for the μ-OR subtype. On this basis, it is shown that phenylazocarboxamides may serve as useful bioisosteric replacements for the widely occurring cinnamide units, witho...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.202000180
更新日期:2020-07-03 00:00:00
abstract::Having recently identified a so-far unexplored area adjacent to the known binding site of allosteric mitogen-activated protein kinase kinase (MEK) inhibitors, we now report an extension of these studies by combining our new side chains with different MEK inhibitor cores in a modular manner. Replacement of the amide he...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201500442
更新日期:2015-12-01 00:00:00
abstract::The serotonin transporter (SERT) is one of the neurotransmitter transporters that plays a critical role in the regulation of endogenous amine concentrations and therefore is an important target for therapeutic agents affecting the central nervous system. The recently published, high resolution X-ray structure of the c...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200600242
更新日期:2007-06-01 00:00:00
abstract::An emerging and attractive target for the treatment of Alzheimer's disease is to inhibit the aggregation of beta-amyloid protein (Abeta). We applied the retro-enantio concept to design an N-methylated peptidic inhibitor of the Abeta42 aggregation process. This inhibitor, inrD, as well as the corresponding all-L (inL) ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200900191
更新日期:2009-09-01 00:00:00
abstract::Metalloproteinases of the astacin family are drawing ever increasing attention as potential drug targets. However, knowledge regarding inhibitors thereof is limited in most cases. Crucial for the development of metalloprotease inhibitors is high selectivity, to avoid side effects brought about by inhibition of off-tar...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201800300
更新日期:2018-08-20 00:00:00
abstract::The histone deacetylase (HDAC) family is a promising drug target class owing to the importance of these enzymes in a variety of cellular processes. Docking studies were conducted to identify novel HDAC inhibitors. Subtle modifications in the recognition domain were introduced into a series of chlamydocin analogues, an...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201300372
更新日期:2014-03-01 00:00:00
abstract::Six phosphorescent (2-phenyl)pyridine (ppy) gold(III) 2,4,6-tris(trifluoromethyl)phenyl (FMes) complexes were synthesized and investigated for their anticancer potential. The compounds demonstrated strong antiproliferative activity, with EC50 values in the low micromolar range, along with significant accumulation in H...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201402446
更新日期:2014-12-01 00:00:00
abstract::A facile protocol that enables synthetic interconversion of CUR-BF2 and CUR compounds is described that significantly widens the preparative scope of curcuminoids, providing access to larger libraries of compounds, thus enabling comparative antiproliferative and apoptotic study of a larger library of synthetic analogs...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201900640
更新日期:2020-02-17 00:00:00
abstract::Phospholipid bilayers represent a complex, anisotropic environment fundamentally different from bulk oil or octanol, for instance. Even "simple" drug association to phospholipid bilayers can only be fully understood if the slab-of-hydrocarbon approach is abandoned and the complex, anisotropic properties of lipid bilay...
journal_title:ChemMedChem
pub_type: 杂志文章,评审
doi:10.1002/cmdc.200900052
更新日期:2009-08-01 00:00:00
abstract::A group of acidic nucleosides were synthesized to develop a new class of ribonuclease A (RNase A) inhibitors. Our recent study on carboxymethylsulfonyl-modified nucleosides revealed some interesting results in RNase A inhibition. This positive outcome triggered an investigation of the role played by secondary sugar hy...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201402179
更新日期:2014-09-01 00:00:00
abstract::Oxoisoaporphine alkaloids are a family of oxoisoquinoline-derived alkaloids that were first isolated from the rhizome of Menispermum dauricum DC. (Menispermaceae). It has been demonstrated that oxoisoaporphine alkaloids possess various biological properties, such as cholinesterase and β-amyloid inhibition, acting as a...
journal_title:ChemMedChem
pub_type: 杂志文章,评审
doi:10.1002/cmdc.201800196
更新日期:2018-07-06 00:00:00
abstract::Detailed information on the metabolic fate of lead compounds can be a powerful tool for an informed approach to the stabilization of metabolically labile compounds in the lead optimization phase. The combination of high performance liquid chromatography (HPLC) with nuclear magnetic resonance (NMR) spectroscopy and mas...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200700203
更新日期:2008-01-01 00:00:00
abstract::Computational chemistry has shown that backbone-alkylated imidazoles ought to be efficient ligands for transition metal catalysts with improved carbene-to-metal donation. In this work, such alkylated imidazoles were synthesized and complexed with silver(I) by means of an eight/nine-step synthetic pathway we devised to...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201500234
更新日期:2015-09-01 00:00:00
abstract::Identification of potent agonists of odorant receptors (ORs), a major class of G protein-coupled receptors, remains challenging due to complex receptor-ligand interactions. ORs are present in both olfactory and non-chemosensory tissues, indicating roles beyond odor detection that may include modulating physiological f...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201600612
更新日期:2017-04-06 00:00:00
abstract::It has been 25 years since the development of the first efficient HIV-1/AIDS treatment. Scientists now know more about the HIV-1 infection life cycle, and more than 30 antiretroviral drugs have been developed, including HIV-1 fusion inhibitors. Fundamental work was begun in the early 1990s and led to the development o...
journal_title:ChemMedChem
pub_type: 杂志文章,评审
doi:10.1002/cmdc.201000289
更新日期:2010-11-08 00:00:00
abstract::A novel and facile synthesis of quinoxalinone derivatives was developed in which a wide range of 3-chloroquinoxalin-2(1H)-ones as key intermediates can be generated chemo- and regioselectively in good yields from corresponding quinoxaline-2,3(1H,4H)-diones. This new protocol is arguably superior, as it allows the desi...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200054
更新日期:2012-05-01 00:00:00
abstract::Herbal medicines (HMs) are an important source of drugs. In this study, an efficient strategy integrating ultrafiltration LC-MS, microplate bioassays, and molecular docking was proposed to screen high-potency enzyme inhibitors from HMs. Using this strategy, the structure-activity relationships (SARs) including binding...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201600489
更新日期:2016-12-06 00:00:00