Abstract:
:Every week, articles disclosing new antifungal leads reported as promising starting points for optimization projects are published. In many cases, the mechanism that accounts for their antifungal activity has not been fully elucidated. More significantly, the detrimental impact that could result from certain embedded chemical features has been underestimated or even overlooked. In the course of our research in the agrochemical area, we have concluded that in many cases such leads are actually nonoptimizable because they either contain what are now recognized as pan assay interference compounds (PAINS) or other promiscuous groups. This article is aimed at highlighting the pitfalls we have encountered and hopefully to steer other research groups away from them.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Pouliot M,Jeanmart Sdoi
10.1021/acs.jmedchem.5b00361subject
Has Abstractpub_date
2016-01-28 00:00:00pages
497-503issue
2eissn
0022-2623issn
1520-4804journal_volume
59pub_type
杂志文章,评审abstract::A series of 9-(hydroxyalkenyl)purines (adenines and 3-deazaadenines), which are analogues of neplanocin A, were synthesized. The analogues were tested as inhibitors of bovine liver and murine L929 cell S-adenosyhomocysteine (AdoHcy) hydrolase (EC 3.3.1.1) and as inhibitors of vaccinia virus replication in murine L929 ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00117a011
更新日期:1988-09-01 00:00:00
abstract::The principle of bioisosterism-similarly shaped molecules are more likely to share biological properties than are other molecules-has long helped to guide drug discovery. An algorithmic implementation of this principle, based on shape comparisons of a single rule-generated "topomer" conformation per molecule, had been...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm990159q
更新日期:1999-09-23 00:00:00
abstract::2,6,8-Trichloro-7-methylpurine (3) was converted to 2-chloro-8,9-dihydro-7-methyl-8-thioxopurin-6(1H)-one (5) by utilizing the difference in reactivity of the 2-, 6-, and 8-positions in the trichloropurine ring system to nucleophilic displacement. Compound 5 was subsequently glycosylated with 1-O-acetyl-2,3,5-tri-O-be...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00170a013
更新日期:1990-08-01 00:00:00
abstract::A series of [(3-aryl-1,2-benzisoxazol-6-yl)oxy]acetic acids was synthesized and tested for diuretic activity in saline-loaded mice and in conscious, water-loaded dogs. The structural requirements for good diuretic activity in both mice and dogs were found to be very specific. In summary, the compounds with the best di...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00343a008
更新日期:1982-01-01 00:00:00
abstract::Neutrophil serine proteases, proteinase 3 (PR3) and human neutrophil elastase (HNE), are considered as targets for chronic inflammatory diseases. Despite sharing high sequence similarity, the two enzymes have different substrate specificities and functions. While a plethora of HNE inhibitors exist, PR3 specific inhibi...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm500782s
更新日期:2014-11-26 00:00:00
abstract::Selenosemicarbazones show marked antitumor activity. However, their mechanism of action remains unknown. We examined the medicinal chemistry of the selenosemicarbazone, 2-acetylpyridine 4,4-dimethyl-3-selenosemicarbazone (Ap44mSe), and its iron and copper complexes to elucidate its mechanisms of action. Ap44mSe demons...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.5b01399
更新日期:2016-01-14 00:00:00
abstract::With a view to identify novel and biocompatible neuroprotectants, we designed nucleoside 5'-thiophosphate analogues, 6-11. We identified 2-SMe-ADP(α-S), 7A, as a most promising neuroprotectant. 7A reduced ROS production in PC12 cells under oxidizing conditions, IC50 of 0.08 vs 21 μM for ADP. Furthermore, 7A rescued pr...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.5b00575
更新日期:2015-11-12 00:00:00
abstract::A new computational method for the in situ generation of small molecules within the binding site of a protein is described. The method has been evaluated using two well-studied systems, dihydrofolate reductase and thymidylate synthase. The method has also been used to guide improvements to inhibitors of HIV-1 protease...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00003a010
更新日期:1995-02-03 00:00:00
abstract::There is urgent need for new therapeutic strategies to fight the global threat of antibiotic resistance. The focus of this Perspective is on chemical agents that target the most common mechanisms of antibiotic resistance such as enzymatic inactivation of antibiotics, changes in cell permeability, and induction/activat...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.7b00215
更新日期:2017-10-26 00:00:00
abstract::Ligands for retinoid X receptors (RXRs), "rexinoids", are attracting interest as candidates for therapy of type 2 diabetes and Alzheimer's and Parkinson's diseases. However, current screening methods for rexinoids are slow and require special apparatus or facilities. Here, we created 7-hydroxy-2-oxo-6-(3,5,5,8,8-penta...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.9b00995
更新日期:2019-10-10 00:00:00
abstract::Through their function as epigenetic readers of the histone code, the BET family of bromodomain-containing proteins regulate expression of multiple genes of therapeutic relevance, including those involved in tumor cell growth and inflammation. BET bromodomain inhibitors have profound antiproliferative and anti-inflamm...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm5010539
更新日期:2014-10-09 00:00:00
abstract::Dual-acting kappa opioid receptor (KOR) agonist and mu opioid receptor (MOR) partial agonist ligands have been put forward as potential treatment agents for cocaine and other psychostimulant abuse. Members of the orvinol series of ligands are known for their high binding affinity to both KOR and MOR, but efficacy at t...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm301543e
更新日期:2013-04-25 00:00:00
abstract::Thirteen newly synthesized or resynthesized diamine-platinum(II) complexes were characterized, and their cytotoxic activities (IC50) were tested on parental and resistant ovarian cancer cell lines. They represent models of conjugates between biologically active vectors and cytotoxic Pt(II) moieties within the "drug ta...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm049508t
更新日期:2005-02-10 00:00:00
abstract::In our efforts to explore marine cyanobacteria as a source of novel bioactive compounds, we discovered a statine unit-containing linear decadepsipeptide, grassystatin A (1), which we screened against a diverse set of 59 proteases. We describe the structure determination of 1 and two natural analogues, grassystatins B ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm9009394
更新日期:2009-09-24 00:00:00
abstract::The EP(3) receptor on the platelet mediates prostaglandin E(2) potentiation of thrombogenic coagonists including collagen and adenosine diphosphate (ADP). A pharmacophore driven approach led to the identification of diverse peri-substituted heterocycles as potent and selective EP(3) receptor antagonists. A simultaneou...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm9005912
更新日期:2010-01-14 00:00:00
abstract::The synthesis of five amino phosphorus derivatives, 1a-e, is described. The derivatives were incorporated into a series (18) of analogues of the 5-14 portion of angiotensinogen, in most cases at the scissile Leu-Val bond. The resultant compounds were tested in vitro for their ability to inhibit human plasma renin. Rep...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00127a041
更新日期:1989-07-01 00:00:00
abstract::Chemically diverse oxysterols were prepared and evaluated for cytotoxicity, aiming to push forward potency and selectivity. They were tested against seven cancer (HT-29, HepG2, A549, PC3, LAMA-84, MCF-7, and SH-SY5Y) and two noncancerous cell lines (ARPE-19 and BJ). The influence of the oxidation pattern on rings A an...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm200803d
更新日期:2011-09-22 00:00:00
abstract::The synthesis of a series N-(4-piperidinyl)-1H-benzimidazol-2-amines and the preliminary evaluation of their in vitro and in vivo antihistaminic activity are described. Cyclodesulfurization of (2-aminophenyl)thioureas with mercury(II) oxide resulted in 2-aminobenzimidazole intermediates, which were monoalkylated on th...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00150a028
更新日期:1985-12-01 00:00:00
abstract::Although cyclooxygenase-1 (COX-1) inhibition is thought to be a major mechanism of gastric damage by nonsteroidal anti-inflammatory drugs (NSAIDs), some COX-1-selective inhibitors exhibit strong analgesic effects without causing gastric damage. However, it is not clear whether their analgesic effects are attributable ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm701191z
更新日期:2008-04-24 00:00:00
abstract::[(Pyridylmethyl)sulfinyl]benzimidazoles 1 (PSBs) are a class of highly potent antisecretory (H+,K+)-ATPase inhibitors which need to be activated by acid to form their active principle, the cyclic sulfenamide 4. Selective inhibitors of the (H+,K+)-ATPase in vivo give rise to the nonselective thiophile 4 solely at low p...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00084a010
更新日期:1992-03-20 00:00:00
abstract::Variation of the bridge linking the heterocyclic ring and p-aminobenzoyl-L-glutamate portions of our previously described classical 2,4-diaminofuro[2,3-d]pyrimidines 1 and 2 are reported as inhibitors of dihydrofolate reductase (DHFR) and thymidylate synthase (TS) and as antitumor agents. Specifically -CH2CH2- and -CH...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00019a009
更新日期:1995-09-15 00:00:00
abstract::Using the crystal structure of an inhibitor complexed with the serine protease thrombin (PDB code ) and the functional group definitions contained within the Catalyst software, a representation of the enzyme's active site was produced (structure-based pharmacophore model). A training set of 16 homologous non-peptide i...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm021028j
更新日期:2003-04-10 00:00:00
abstract::A number of cycloalkyl substituents (from C-3 to C-8) have been introduced on the 6-amino group of adenosine, 1-deazaadenosine, and 2'-deoxyadenosine, bearing or not a chlorine atom at the 2-position, to evaluate the influence on the A(1) and A(2A) affinity of steric hindrance and lipophilicity. Furthermore, the guano...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm9911231
更新日期:2000-01-27 00:00:00
abstract::Novel 19-norvitamin D analogues (ADYW1-4, 5a-d) in which an adamantyl diyne side chain is attached directly to the 17-position of the D ring are designed and stereoselectively synthesized. The adamantane ring of these analogues was expected to interfere with helix 12 (H12, activation function 2) of the vitamin D recep...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.5b00792
更新日期:2015-12-24 00:00:00
abstract::Cyclin-dependent kinase 2 (CDK2) drives the progression of cells into the S- and M-phases of the cell cycle. CDK2 activity is largely dispensable for normal development, but it is critically associated with tumor growth in multiple cancer types. Although the role of CDK2 in tumorigenesis has been controversial, emergi...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章,评审
doi:10.1021/acs.jmedchem.8b01469
更新日期:2019-05-09 00:00:00
abstract::Two 12-amino-6,7,8,11-tetrahydro-7,11-methanocycloocta[b]quinoline derivatives [9-Me(Et)] (syn-huprines) have been obtained by condensation of known 7-alkylbicyclo[3.3.1]non-6-en-3-ones with 2-(trifluoromethyl)aniline, followed by basic cyclization of the resulting imine, and chromatographic separation of the regioiso...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm010949b
更新日期:2001-12-20 00:00:00
abstract::New potent and selective KISS1R agonists were designed using a combination of rational chemical modifications of the endogenous neuropeptide kisspeptin 10 (KP10). Improved resistance to degradation and presumably reduced renal clearance were obtained by introducing a 1,4-disubstituted 1,2,3-triazole as a proteolysis-r...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm5019675
更新日期:2015-04-23 00:00:00
abstract::Several new phospholipid-ara-C conjugates have been prepared and tested as prodrugs of the parent ara-C. The new derivative include ara-CMP-L-dipalmitin, ara-CDP-L-distearin, ara-CDP-L dimyristin, ara-CDP-L-diolein, and the radioactively labeled derivative ara-CDP-L-di[1-14C]palmitin. In addition, the unusually stable...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00353a010
更新日期:1982-11-01 00:00:00
abstract::Angiotensin-converting enzyme 2 (ACE2), a recently identified human homologue of angiotensin-converting enzyme, is a zinc metallocarboxypeptidase which may play a unique role in cardiovascular and renal function. Here we report the discovery of potent and selective inhibitors of ACE2, which have been identified by eva...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm701275z
更新日期:2008-04-10 00:00:00
abstract::A new group of potent inhibitors of glutamine synthetase was designed and synthesized. The X-ray structure of bacterial glutamine synthetase complexed with phosphinothricin was used for computer-aided structure-based design of the inhibitors, in which the methyl group of phosphinothricin was chosen as the modification...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm050474e
更新日期:2005-10-06 00:00:00