Abstract:
:In the search for novel hybrid molecules by fusing two biologically active scaffolds into one heteromeric chemotype, we found that hybrids of azithromycin and ciprofloxacin/gatifloxacin 26j and 26l can inhibit the supercoiling activity of E. coli gyrase by poisoning it in a way similar to fluoroquinolones. This may modestly contribute to their potencies, which are equal to ciprofloxacin against constitutively resistant Staphylococcus aureus, whose growth is not inhibited by the presence of macrolides. In contrast, introduction of quinolines (the 3-quinoline 26b and the 6-quinoline 26o) with an optimized rigid spacer at the 6-OH of azithromycin acylides did not exert significant potency against constitutively resistant S. aureus, despite the fact that the quinoline-containing compounds, exemplified by 26o, were as active as telithromycin against susceptible, inducibly- and efflux-resistant pathogens. The novel dual modes of action involving protein synthesis inhibition and poisoning DNA replication may pave the way for restoration of antibacterial activities of the current macrolides against constitutively resistant clinical isolates.
journal_name
Eur J Med Chemjournal_title
European journal of medicinal chemistryauthors
Fan BZ,Hiasa H,Lv W,Brody S,Yang ZY,Aldrich C,Cushman M,Liang JHdoi
10.1016/j.ejmech.2020.112222subject
Has Abstractpub_date
2020-05-01 00:00:00pages
112222eissn
0223-5234issn
1768-3254pii
S0223-5234(20)30189-6journal_volume
193pub_type
杂志文章abstract::Molecular orbital energies of energetically minimized series of extended aromatic and aminoalkyl side chain substituted phenothiazine compounds have been considered with respect to charge transfer (CT) binding properties to P-glycoprotein (P-gp) amino acids of the first P-gp loop. A dependency of decreasing energies o...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2005.11.011
更新日期:2006-04-01 00:00:00
abstract::The PF74 binding site in HIV-1 capsid protein (CA) is a compelling antiviral drug target. Although PF74 confers mechanistically distinct antiviral phenotypes by competing against host factors for CA binding, it suffers from prohibitively low metabolic stability. Therefore, there has been increasing interest in designi...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2020.112626
更新日期:2020-10-15 00:00:00
abstract::Based on the literature-reported compensatory effect of PI3K on Abl inhibition and the improved preclinical effect of drug combination of Abl and PI3K inhibitors, a series of compounds bearing novel scaffold of (S)-3-aminopyrrolidine was identified as Abl and PI3K dual inhibitors through support vector machine screeni...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2011.01.020
更新日期:2011-04-01 00:00:00
abstract::A series of 2-(benzylthio)-5-aryloxadiazole derivatives have been designed and synthesized, and their biological activities are also evaluated for EGFR inhibitory activity. Fourteen compounds among the twenty compounds are reported for the first time. Their chemical structures are characterized by (1)H NMR, MS, and el...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2011.11.015
更新日期:2012-01-01 00:00:00
abstract::With an aim of developing novel protein tyrosine phosphatase (PTP) 1B inhibitors based on sugar scaffolds, a focused library of benzyl 6-triazolo(hydroxy)benzoic glucosides was efficiently constructed via the modular and selective Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddtion (click chemistry). These glycoconj...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2011.06.025
更新日期:2011-09-01 00:00:00
abstract::Oxyprenylated secondary metabolites from plants, fungi, and bacteria, and their semisynthetic derivatives have been subject of growing interest during the last decade. Such natural products in fact have been discovered as potentially novel lead compounds for a series of pharmacological activities, mainly in terms of a...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章,评审
doi:10.1016/j.ejmech.2017.08.038
更新日期:2018-06-10 00:00:00
abstract::Wnt signaling pathway plays a critical role in numerous cellular processes, including tumor initiation, proliferation, invasion/infiltration, metastasis formation and resistance to chemotherapy. In a drug discovery project aimed at the identification of inhibitors of the canonical Wnt pathway, we selected a series of ...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2015.03.055
更新日期:2015-05-05 00:00:00
abstract::In this study, a series of benzimidazoles bearing thiosemicarbazide chain or triazole and thiadiazole rings were designed and synthesized. Crystal and molecular structure of the compound 5c has been characterized by single crystal X-ray crystallographic analysis. EGFR kinase inhibitory potencies of synthesized compoun...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2019.04.012
更新日期:2019-07-01 00:00:00
abstract::Quinolones are widely used broad-spectrum antibacterials with incomplete elucidated mechanism of action. Here, molecular basis for the antibacterial action of quinolones, from target to network, is fully discussed and updated. Quinolones trap DNA gyrase or topoisomerase IV to form reversible drug-enzyme-DNA cleavage c...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章,评审
doi:10.1016/j.ejmech.2013.01.057
更新日期:2013-08-01 00:00:00
abstract::NOD1 and NOD2 are pattern recognition receptors that have important roles in innate immune responses. Although their overactivation has been linked to a number of diseases, NOD2 in particular remains a virtually unexploited target in this respect, with only one structural class of antagonist reported. To gain insight ...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2020.112089
更新日期:2020-03-15 00:00:00
abstract::Tuberculosis (TB) remains among the world's great public health challenges. Worldwide resurgence of TB is due to two major problems: the AIDS epidemic, which started in the mid-1980s, and the outbreak of multidrug resistant (MDR) TB. Thus, there is an urgent need for anti-TB drugs with enhanced activity against MDR st...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2010.07.020
更新日期:2010-10-01 00:00:00
abstract::Two novel series of 4-thiazolidinone derivatives, namely 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid [2-(5-nitro-2-furyl/substituted phenyl)-4-thiazolidinone-3-yl]amides (5a-g) and 2-(2',4'-difluoro-4-hydroxybiphenyl-3-carbonylhydrazono)-3-alkyl/aryl-4-thiazolidinones (6a-e) together with 5-(2',4'-difluoro-4-hy...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2005.11.005
更新日期:2006-03-01 00:00:00
abstract::ALK and ROS1 kinases have become promising therapeutic targets since Crizotinib was used to treat non-small-cell lung cancer clinically. Aiming to explore new potent inhibitors, a series of 2-amino-4-(1-piperidine) pyridine derivatives that stabilized a novel DFG-shifted conformation in the kinase domain of ALK were d...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2019.06.043
更新日期:2019-10-01 00:00:00
abstract::3-(Alkyl(dialkyl)amino)benzothieno[2,3-f]quinazolin-1(2H)-ones (4-9) have been designed using Ellipticine structure as a model, replacing the carbazole core and the pyridine ring with a dibenzothiophene and a pyrimidine moiety, respectively. New benzothienoquinazolinones (4-9) have been synthesized by a simple one-pot...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2019.111583
更新日期:2019-11-01 00:00:00
abstract::During a screening for compounds that could act against Mycobacterium tuberculosis, a series of new cellular antiproliferative agents was identified. The most cytotoxic molecules were evaluated against a panel of human cell lines derived from hematological and solid human tumors. In particular, (E)-2-(1H-benzo[d] [1,2...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2011.06.018
更新日期:2011-09-01 00:00:00
abstract::A glycoside prodrug of 4-aminosalicylic acid (4-ASA) with d-glucose was synthesized for targeted drug delivery to inflammatory bowel. The in vitro assessment of 4-aminosalicylic acid-β-O-glucoside (4-ASA-Glu) as a colon-specific prodrug was studied using colitis rat with the healthy one as control. The stability studi...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2015.12.021
更新日期:2016-01-27 00:00:00
abstract::We here describe the preparation of a series of hybrid molecules containing a combretastatin A-4 moiety and a pironetin analogue fragment connected through a spacer of variable length which includes a 1,2,3-triazole ring. The cytotoxic activities of these compounds have been measured. Relations between structure and c...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2014.09.053
更新日期:2014-11-24 00:00:00
abstract::The design and synthesis of a series of new fluorescent coumarin-containing melatonin analogues is presented. The combination of high-binding affinities for human melatonergic receptors (h-MT₁R and h-MT₂R) and fluorescent properties, derived from the inclusion of melatonin pharmacophoric elements in the coumarin scaff...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2015.09.003
更新日期:2015-10-20 00:00:00
abstract::On the basis of computer prediction of biological activity by PASS and toxicity by DEREK, the most promising 32-alkylaminoacyl derivatives of 3-aminobenzo[d]isothiazole were selected for possible local anaesthetic action. This action was evaluated using an in vitro preparation of the isolated sciatic nerve of the rat ...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2008.04.006
更新日期:2009-02-01 00:00:00
abstract::Researches on tumor-associated antigen have become a hot target in immunotherapy, but it stagnated in the pre-clinical/clinical stages. Here, we developed a series of MAGE-A1-restricted antigenic peptides, which exhibited prominent inhibiting effect on specific breast cancer. Peptides were synthesized by Fmoc solid ph...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2020.112051
更新日期:2020-03-01 00:00:00
abstract::A series of anthracenone-based oxime ethers and -esters were synthesized in order to evaluate their antiproliferative activity. Several investigated compounds displayed strong antiproliferative activity against K562 leukemia cells and proved to be strong inhibitors of tubulin polymerization. In this context, anthracen...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2010.04.019
更新日期:2010-08-01 00:00:00
abstract::The pure enantiomers of the N-(2-, 3-, and 4-(2-aminocyclopropyl)phenyl)benzamides hydrochlorides 11a-j were prepared and tested against LSD1 and MAO enzymes. The evaluation of the regioisomers 11a-j highlighted a net increase of the anti-LSD1 potency by shifting the benzamide moiety from ortho to meta and mainly to p...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2015.02.060
更新日期:2015-04-13 00:00:00
abstract::A series of 7-[4-(5-aryl-1,3,4-oxadiazole-2-yl)piperazinyl] quinolones (I-XXI) were synthesized using an appropriate synthetic route and characterized by elemental and spectral analysis. The antibacterial activities of all the synthesized compounds were evaluated against identifiable bacterial strains. Compounds III, ...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2011.04.035
更新日期:2011-09-01 00:00:00
abstract::N(6)-Monoalkylated, N(6)-dialkylated and N(6)-acylated (R(P))-adenosine 3',5'-cyclic phosphorothioic acids have been prepared by stereoselective syntheses from cAMP for a study of protein kinase A antagonist activity. The antagonist activity of the parent primary 6-amino cAMP derivative was reduced after N-monoalkylat...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2011.10.003
更新日期:2011-12-01 00:00:00
abstract::Several new benzamides 4a-q were synthesized by stirring in pyridine the acid chlorides 3a-q with the appropriate anthranilamide derivatives 2a-g. Some of the synthesized compounds were evaluated for their in vitro antiproliferative activity against a panel of 5 human cell lines (K562 human chronic myelogenous leukemi...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2013.04.068
更新日期:2013-07-01 00:00:00
abstract::Pyrazine-fused 23-hydroxybetulinic acid was synthesized by introducing a pyrazine ring between C-2 and C-3 position and further modifications were carried out by substitution of C-28 carboxyl group by ester and amide linkage to enhance the antitumor activity. The biological screening results showed that all of the der...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2015.04.057
更新日期:2015-06-05 00:00:00
abstract::A phytochemical investigation of Inula falconeri, a plant endemic to the Himalayas, afforded 10 new sesquiterpenoids and 26 known sesquiterpene lactones, including those bearing guaiane, pseudoguaiane, xanthane, eudesmane, germacrane, rare secocaryophyllane, chromolaevane, and carabrane frameworks. The structures were...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2011.08.047
更新日期:2011-11-01 00:00:00
abstract::To evaluate N-hydroxyurea as zinc binding group in the design of MMP inhibitors, two peptidyl 1-hydroxyureas were prepared by N-hydroxycarbamoylation of the diastereomeric dipeptides H-Leu-Phe-NHMe and H-D-Leu-Phe-NHMe. Peptidyl 1-hydroxyureas were more potent than the parent peptides, but dramatically weaker (4-5 ord...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2007.07.002
更新日期:2008-05-01 00:00:00
abstract::The design of novel antitumor agents allowing the destruction of malignant cells while sparing healthy tissues is one of the major challenges in medicinal chemistry. In this context, the use of non-toxic prodrugs programmed to be selectively activated by beta-glucuronidase present at high concentration in the microenv...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2013.12.045
更新日期:2014-03-03 00:00:00
abstract::A novel series of the biheterocycles-based compounds with core structure distinguished from combretastatin A-4 (1) and colchicine (5) have been synthesized and evaluated as potent anti-mitotic agents. Compound 1-(4'-Indolyl and 6'-quinolinyl)-4,5,6-trimethoxyindoles 13 and 19 showed substantial anti-proliferative acti...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2011.04.065
更新日期:2011-09-01 00:00:00