Abstract：
:Using a combination of docking and molecular dynamics simulations, we predicted that p-hydroxylation by CYP1A2 would be the main metabolic pathway for the 1-[1-(4-chlorophenyl)-1H-4pyrazolylmethyl] phenylhexahydropiperazine, LASSBio-579 (3). As the result of a screening process with strains of filamentous fungi, Cunninghamella echinulata ATCC 9244 was chosen to scale up the preparation of the p-hydroxylated metabolite (4). About 30 min after i.p. administration of (3) to rats was identified as the p-hydroxylated metabolite, confirming our in silico previsions. Chemical synthesis of the metabolite was performed and allowed its pharmacological evaluation in binding assays revealing its high affinity for D2 and D4 receptors, indicating that this metabolite should participate to the antipsychotic effect of (3) in vivo. Furthermore, we report here that both (3) and its p-hydroxylated metabolite (4) have a much lower affinity than clozapine for two receptors involved in adverse reactions. Voltammetric assays were useful to understand the redox profile of (3).
journal_name
Eur J Med Chemjournal_title
European journal of medicinal chemistryauthors
Gomes TF,Pompeu TE,Rodrigues DA,Noël F,Menegatti R,Andrade CH,Sabino JR,Gil ES,Dalla Costa T,Betti AH,Antonio CB,Rates SM,Fraga CA,Barreiro EJ,de Oliveira Vdoi
10.1016/j.ejmech.2012.08.011subject
Has Abstractpub_date
2013-04-01 00:00:00pages
214-21eissn
0223-5234issn
1768-3254pii
S0223-5234(12)00490-4journal_volume
62pub_type
杂志文章abstract：:Alzheimer's disease (AD) is associated with multifactorial neuropathological conditions, which include cholinergic deficit, amyloid-beta plaques formation, loss of neuronal plasticity and neuronal death. Treating such multifactorial conditions with a single target directed approach is considered to be inadequate. Acco...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2019.111613
更新日期：2019-11-15 00:00:00
abstract：:Kinetic analysis of the mode of inhibition of cathepsin L by KGP94, a lead compound from a privileged library of functionalized benzophenone thiosemicarbazone derivatives, demonstrated that it is a time-dependent, reversible, and competitive inhibitor of the enzyme. These results are consistent with the formation of a...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2012.10.039
更新日期：2012-12-01 00:00:00
abstract：:The 4-substituted 1,2,3-triazole core in designed coumarin hybrids (4-35) with diverse physicochemical properties was introduced by eco-friendly copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition under microwave irradiation. Coumarin-1,2,3-triazole-benzofused heterocycle hybrids emerged as the class of compounds ex...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2016.08.062
更新日期：2016-11-29 00:00:00
abstract：:Some new ethyl 2-[3-(4-unsubstituted or 4-substituted phenylsufonyl)ureido]-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxylates 3a-c, 2-[3-(phenylsulfonyl)ureido]-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carbohydrazides 4a-f, 3-phenylsulfonyl-6,7,8,9-tetrahydro-5H-cyclohepta[1',2':4,5]thieno[2,3-d]pyrimi...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2009.11.014
更新日期：2010-02-01 00:00:00
abstract：:In last few decades, though significant progress has been made in the treatment and control strategies of tubercular infections by introducing new diagnostic and monitoring tools and combination therapy, it still continues to be a severe problem. Thus with the aim of developing novel molecules with improved potency fo...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2006.12.001
更新日期：2007-06-01 00:00:00
abstract：:The synthesis and biological activities of acidic, basic and neutral types of butyric acid (BA) prodrugs possessing increased aqueous solubility are described. The compounds are butyroyloxyalkyl derivatives of carboxylic acids, which possess functionalities suitable for aqueous solubilization. The anticancer activity ...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/s0223-5234(00)01199-5
更新日期：2001-01-01 00:00:00
abstract：:New nitrosoureido derivatives of di- or tri-deoxy-sugars have been synthesized. Very potent antitumour activity against L1210 leukaemia was exhibited by the compounds derived from methyl 3-amino-3, 4-dideoxy-beta- and alpha- and 4-amino-2,4-dideoxy-beta- and alpha-D-arabino-hexopyranosides, 24, 26, 28 and 29, respecti...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/s0223-5234(00)00114-8
更新日期：2000-01-01 00:00:00
abstract：:Alzheimer's disease is a progressive brain disorder with characteristic symptoms and several pathological hallmarks. The concept of "one drug, one target" has not generated any new drugs since 2004. The new era of drug development in the field of AD builds upon rationally designed multi-target directed ligands that ca...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2020.113112
更新日期：2021-02-05 00:00:00
abstract：:Herein we report the straightforward preparation of novel conformationally-restricted steroids from trans-androsterone and estrone, decorated with spiranic oxazolidin-2-one or 2-aminooxazoline motifs at C-17 as potential antiproliferative agents. Such unprecedented pharmacophores were accessed using an aminomethylalco...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2017.10.063
更新日期：2018-01-01 00:00:00
abstract：:A series of 3-arylidene-5-(4-chloro-phenyl)-2(3H)-furanones (2-13) and their nitrogen analogues 1-benzylpyrrolones (14-18) were synthesized. The compounds were evaluated for their anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation actions. Some of the newly synthesized compounds showed good anti-inflamma...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2008.10.030
更新日期：2009-06-01 00:00:00
abstract：:Insulin-degrading enzyme, IDE, is a metalloprotease implicated in the metabolism of key peptides such as insulin, glucagon, β-amyloid peptide. Recent studies have pointed out its broader role in the cell physiology. In order to identify new drug-like inhibitors of IDE with optimal pharmacokinetic properties to probe i...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2019.06.057
更新日期：2019-10-01 00:00:00
abstract：:A series of sulfapyridine-polyhydroxyalkylidene (or arylidene)-imino derivatives (Schiff's bases) 2a-c and 4a-e were prepared by condensation of 4-amino-N-pyridin-2-ylbenzenesulfonamide (1) with different monosaccharides or with aromatic aldehydes. Treatment of 2a-c with thioglycolic acid led to the formation of the C...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2009.10.044
更新日期：2010-02-01 00:00:00
abstract：:Melanoma is an aggressive form of skin cancer and it is generally associated with poor prognosis in patients with late-stage disease. Due to the increasing occurrence of melanoma, there is a need for the development of novel therapies. A new series of diarylamide and diarylurea derivatives containing imidazo[1,2-a]pyr...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2015.12.001
更新日期：2016-01-27 00:00:00
abstract：:Malignant tumor cells have been found to have high levels of reactive oxygen species such as hydrogen peroxide (H2O2), supporting the hypothesis that a prodrug could be activated by intracellular H2O2 and lead to a potential antitumor therapy. In this study, the 7-ethyl-10-boronic acid camptothecin (B1) was synthesize...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2016.03.063
更新日期：2016-06-30 00:00:00
abstract：:Antimicrobial resistance is one of the greatest challenges facing the world today. In the United States alone, it is responsible for the death of more than 20,000 people each year. DNA gyrase, a well-validated drug target, is involved in bacterial DNA replication, repair and decatenation. Currently, the fluoroquinolon...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1016/j.ejmech.2020.112326
更新日期：2020-08-01 00:00:00
abstract：:Six series of 2-substituted 4-aminobutanamide derivatives were synthesized and evaluated for their ability to inhibit GABA transport proteins mGAT1-4 stably expressed in HEK-293 cell lines. The pIC50 values determined were in the range 4.23-5.23. Two compounds (15b and 15c) were selected for further in vitro studies. ...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2014.06.024
更新日期：2014-08-18 00:00:00
abstract：:Eukaryotic translation initiation factor 4E (eIF4E) is a key player in the initiation of cap-dependent translation through recognition of the m7GpppX cap at the 5' terminus of coding mRNAs. As eIF4E overexpression has been observed in a number of human diseases, most notably cancer, targeting this oncogenic translatio...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2019.01.080
更新日期：2019-03-15 00:00:00
abstract：:We have previously demonstrated that pyrrolo[2,3-a]carbazole-3-carbaldehydes are potent Pim kinase inhibitors with in vitro antiproliferative activities. In the present study, we report the synthesis of new pyrrolocarbazoles substituted at the N-10 position. When their ability to inhibit Pim kinase activities were eva...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2012.02.009
更新日期：2012-04-01 00:00:00
abstract：:Developing new therapeutic strategies to overcome drug resistance of cancer cells is an ongoing endeavor. From among 2 million chemicals, we identified ethyl 4-oxo-2-phenyl-1,4-dihydroquinoline-6-carboxylate (AS1712) as a low-toxicity inhibitor of lung cancer cell proliferation and xenograft tumor growth. We show that ...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2019.111584
更新日期：2019-11-01 00:00:00
abstract：:Three, new, fully synthetic glycosylated isomalyngamide A analogs 4-6 were prepared and evaluated for their anti-migratory activities in human breast cancer cells. The results of the study show that two glycosylated derivatives 4 and 5, containing mannose and galactose appendages, suppress metastatic events (e.g., mig...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2013.03.044
更新日期：2013-06-01 00:00:00
abstract：:Three new Amaryllidaceae alkaloids, named zephycandidines I-III (1-3), were isolated from Zephyranthes candida. The structures of 1-3 were elucidated by spectroscopic analyses including HRESIMS, 1H NMR, 13C NMR, DEPT, HSQC, 1H-1H COSY, HMBC, ROESY, and electronic circular dichroism (ECD), as well as ECD calculation. T...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2016.10.057
更新日期：2017-02-15 00:00:00
abstract：:The oxidation of bioorganic materials by air and, particularly, the oxidative stress involved in the cell loss and other pathologies associated with neurodegenerative diseases (NDs) are of enormous social and economic importance. NDs generally involve free radical reactions, beginning with the formation of an initiati...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1016/j.ejmech.2017.03.061
更新日期：2017-06-16 00:00:00
abstract：:A data set of 389 compounds, active in the central nervous system (CNS) and divided into eight classes according to the receptor type, was extracted from the RBI database and analyzed by Self-Organizing Maps (SOM), also known as Kohonen Artificial Neural Networks. This method gives a 2D representation of the distribut...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/s0223-5234(01)01233-8
更新日期：2001-04-01 00:00:00
abstract：:Following promising recent in vitro and in vivo studies of the anticancer efficacies of heterometallic titanocene-gold chemotherapeutic candidates against renal cancer, we report here on the synthesis, characterization, stability studies and biological evaluation of a new titanocene complex containing a gold-triethylp...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2018.10.034
更新日期：2019-01-01 00:00:00
abstract：:The CXCR4/CXCL12 chemokine axis can chemotactically accumulate inflammatory cells to local tissues and regulate the release of inflammatory factors. Developing novel CXCR4 modulators may provide a desirable strategy to control the development of inflammation. A series of novel hybrids were designed by integrating the ...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2018.02.085
更新日期：2018-04-25 00:00:00
abstract：:Matrix metalloproteinases (MMPs) are important factors in gliomas since these enzymes facilitate invasion into the surrounding brain and participate in neovascularization. In particular, the gelatinases (MMP-2 and MMP-9), and more recently MMP-25, have been shown to be highly expressed in gliomas and have been associa...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2011.03.033
更新日期：2011-07-01 00:00:00
abstract：:A series of novel ketoprofen derivatives 4a-j bearing both amide and carbamate functionalities were prepared using benzotriazole. Selective reduction of ketoprofen produced hydroxy derivative 2, which reacts with one or 2 mol of 1-benzotriazole carboxylic acid chloride (1) gave benzotriazole derivatives 3a and 3b resp...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章,收录出版
doi：10.1016/j.ejmech.2010.04.008
更新日期：2010-07-01 00:00:00
abstract：:Isocombretastatins are the not isomerizable 1,1-diarylethene isomers of combretastatins. Both families of antimitotics are poorly soluble and new analogs with improved water solubility are needed. The ubiquitous 3,4,5-trimethoxyphenyl ring and most of its replacements contribute to the solubility problem. 39 new compo...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2020.112933
更新日期：2021-01-01 00:00:00
abstract：:A series of bis-salicylaldimine ligands bearing two ON-donor functions were reacted with dichloro(p-cymene)ruthenium(II) dimer in the presence of base (NaOAc) and a series of four dimetallic Ru(II) arene complexes (Ru(p-cymene))2(bis-salicylaldimine)Cl2 (C1C4) were prepared. These complexes were obtained in excellent ...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2018.08.054
更新日期：2018-09-05 00:00:00
abstract：:A new efficient synthetic method to obtain prokineticin receptor antagonists based on the triazinedione scaffold is described. In this procedure the overall yield improves from 13% to about 54%, essentially for two factors: 1) N-(chlorocarbonyl) isocyanate is no more used, it represents the yield limiting step with an...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2014.05.030
更新日期：2014-06-23 00:00:00
