Trisubstituted Imidazoles Research Articles

Characterization of LY2228820 Dimesylate, a Potent and Selective Inhibitor of p38 MAPK with Antitumor Activity

p38α mitogen-activated protein kinase (MAPK) is activated in cancer cells in response to environmental factors, oncogenic stress, radiation, and chemotherapy. p38α MAPK phosphorylates a number of substrates, including MAPKAP-K2 (MK2), and regulates the production of cytokines in the tumor microenvironment, such as TNF-α, interleukin-1β (IL-1β), IL-6, and CXCL8 (IL-8). p38α MAPK is highly expressed in human cancers and may play a role in tumor growth, invasion, metastasis, and drug resistance. LY2228820 dimesylate (hereafter LY2228820), a trisubstituted imidazole derivative, is a potent and selective, ATP-competitive inhibitor of the α- and β-isoforms of p38 MAPK in vitro (IC(50) = 5.3 and 3.2 nmol/L, respectively). In cell-based assays, LY2228820 potently and selectively inhibited phosphorylation of MK2 (Thr334) in anisomycin-stimulated HeLa cells (at 9.8 nmol/L by Western blot analysis) and anisomycin-induced mouse RAW264.7 macrophages (IC(50) = 35.3 nmol/L) with no changes in phosphorylation of p38α MAPK, JNK, ERK1/2, c-Jun, ATF2, or c-Myc ≤ 10 μmol/L. LY2228820 also reduced TNF-α secretion by lipopolysaccharide/IFN-γ-stimulated macrophages (IC(50) = 6.3 nmol/L). In mice transplanted with B16-F10 melanoma, tumor phospho-MK2 (p-MK2) was inhibited by LY2228820 in a dose-dependent manner [threshold effective dose (TED)(70) = 11.2 mg/kg]. Significant target inhibition (>40% reduction in p-MK2) was maintained for 4 to 8 hours following a single 10 mg/kg oral dose. LY2228820 produced significant tumor growth delay in multiple in vivo cancer models (melanoma, non-small cell lung cancer, ovarian, glioma, myeloma, breast). In summary, LY2228820 is a p38 MAPK inhibitor, which has been optimized for potency, selectivity, drug-like properties (such as oral bioavailability), and efficacy in animal models of human cancer.

Synthesis of trisubstituted imidazoles via a convergent reaction network from methyl ketones and benzoins

A novel method for constructing trisubstituted imidazoles has been created using simple and readily available aromatic ketones, benzoins, and ammonium acetate as starting materials. The new synthetic strategy utilized a convergent integration of two self-labor domino sequences, providing a typical example for logical self-organization synthesis.

Papain Catalyzed: Multicomponent Synthesis of Trisubstituted Imidazoles

A reliable synthetic method has been developed for 2, 4, 5-trisubstituted imidazole from benzil, ammonium acetate, and aromatic aldehyde by using papain a non toxic and inexpensive catalyst. The Structural features have been arrived at from their analytical data, IR, Mass, 1H NMR. The antibacterial activity of all synthesized compound has been performed by using filter paper disc method against gram positive and gram negative bacteria.We observed that 4a –compound is more active against gram +ve S. Typhi at lower concentration 4f less active against gram +ve S. Typhi and gram –ve E. Coli

Simple and efficient synthesis of trisubstituted imidazoles

The thermally activated or microwave-induced one-pot three-component condensation of arylglyoxal hydrates, 1,3-dimethylbarbituric acid, and guanidine salts or methylisothiuronium hydroiodide gave respectively 2-amino-5-aryl- and 5-aryl-2-methylsulfanylimidazoles containing a 1,3-dimethylbarbituric acid residue. An unexpected course for the condensation was discovered in the case of guanidine hydrochloride, leading to 5-(2-aryl-2-oxoethyl)-1,3-dimethylbarbituric acids. 2-Amino-2-arylimidazoles under the conditions of such three-component condensation formed Michael adducts involving 5-(2-aryl-2- oxoethylidene)-1,3-dimethylbarbituric acids and the C-5 atom of the imidazole ring.

Trisubstituted imidazoles as positive modulators of metabotropic glutamate receptor subtype 5.

ADVERTISEMENT RETURN TO ISSUEPREVPatent HighlightNEXTTrisubstituted Imidazoles as Positive Modulators of Metabotropic Glutamate Receptor Subtype 5Gerard Rosse*View Author Information Structure Guided Chemistry, Dart Neuroscience LLC, 7473 Lusk Boulevard, San Diego, California 92121, United States, and Adjunct Associate Professor, Department of Pharmacology and Physiology, College of Medicine, Drexel University, New College Building, 245 North 15th Street, Philadelphia, Pennsylvania 19102, United States*E-mail: [email protected]Cite this: ACS Med. Chem. Lett. 2013, 4, 9, 819–821Publication Date (Web):August 6, 2013Publication History Received16 July 2013Published online6 August 2013Published inissue 12 September 2013https://doi.org/10.1021/ml4002776Copyright © 2013 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views428Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (393 KB) Get e-AlertsSUBJECTS:Imidazoles,Modulators,Monomers,Peptides and proteins,Receptors Get e-Alerts

ChemInform Abstract: Synthesis of Di‐ and Tri‐Substituted Imidazole‐4‐carboxylates via PBu3‐Mediated [3 + 2] Cycloaddition

Abstractof Δ2‐oxazoline generated in situ from amidoacetic acids (I) and cyanoformate (II)

Sulphamic acid-functionalized magnetic Fe3O4 nanoparticles as recyclable catalyst for synthesis of imidazoles under microwave irradiation

Trisubstituted imidazoles have been synthesized in high yield in the presence of sulphamic acid-functionalized magnetic Fe3O4 nanoparticles (SA–MNPs) as a novel solid acid catalyst under solvent-free classical heating conditions or using microwave irradiation. The heterogeneous catalyst could be recovered easily and reused many times without significant loss of catalytic activity. An efficient procedure for the synthesis of imidazoles has been developed by condensation reaction of 1, 2-diketones, aromatic aldehydes, and ammonium acetate using sulphamic acid-functionalized Fe3O4 nanoparticles under microwave irradiation. This method offers several advantages including high yield, short reaction time, simple work-up procedure and recyclability of the magnetic catalyst.

Synthesis of Trisubstituted Imidazoles via Oxidative Diamination of Alkynes

Key words imidazoles - copper catalysis - oxidative deamination - alkynes

ChemInform Abstract: Convenient Synthesis of Highly Substituted Imidazole Derivatives

Abstractfrom α‐acetoxy‐α‐chloro‐‐keto‐esters (I)

Nano-Sized and -Crystalline Sulfated Zirconia Solid Acid Catalysts for Organic Synthesis

Sulfated Zirconia (SZ) has opened up a very interesting area for application predominantly as catalyst for various acid catalyzed organic syntheses and transformation reactions. Catalytic properties of SZ vary with methods of preparation. Lot of efforts is made to modify SZ to increase reactivity and stability of the catalyst. This review focuses on the individual synthesis routes to prepare nano-sized and –crystalline SZ, short discussion on its characterization and exhaustive survey on its utility in organic chemistry for the development of new synthetic methodologies, which provide simple direction having enormous practical significance. As can be realized, the nano-sized and –crystalline SZ as solid acid catalyst exhibits exceptionally better catalytic activity and selectivity for the synthesis of trisubstituted and tetrasubstituted imidazoles, acetyl salicylic acid, dypnone, esterification of acetic acid, caprylic acid and so on.

ChemInform Abstract: Rapid Access of Some Trisubstituted Imidazoles from Benzil Condensed with Aldehydes and Ammonium Acetate Catalyzed by L‐Cysteine.

ChemInform Abstract: Rapid Access of Some Trisubstituted Imidazoles from Benzil Condensed with Aldehydes and Ammonium Acetate Catalyzed by L‐Cysteine.

Tri-substituted imidazole analogues of SB203580 as inducers for cardiomyogenesis of human embryonic stem cells

The p38α mitogen-activated protein kinase (MAPK) inhibitor SB203580 had been reported to enhance the cardiomyogenesis of human embryonic stem cells (hESCs). To investigate if tri-substituted imidazole analogues of SB203580 are equally effective inducers for cardiomyogenesis of hESCs, and if there is a correlation between p38α MAPK inhibition and cardiomyogenesis, we designed and synthesized a series of novel tri-substituted imidazoles with a range of p38α MAPK inhibitory activities. Our studies demonstrated that suitably designed analogues of SB203580 can also be inducers of cardiomyogenesis in hESCs and that cell growth is affected by changes in the imidazole structures.

Article Synthesis and Trypanocidal Activity of Novel 2,4,5-Triaryl-N-Hydroxylimidazole Derivatives

Herein, we report the design, synthesis and trypanocidal activity of some novel trisubstituted imidazole derivatives. These heterocyclic derivatives were structurally planned by exploring the concept of molecular hybridisation between two arylhydrazones derived from megazol, which has potent trypanocidal activity. The trypanocidal activity of these triarylimidazole derivatives was evaluated against infective trypomastigote forms of T. cruzi and the derivative 2'-(4-bromophenyl)-1-methyl-5'-phenyl-1H,3'H-2,4'-biimidazol-3'-ol showed moderate biological activity (IC50 = 23.9 µM) when compared to benznidazole, a standard trypanocidal drug. These compounds did not present cytotoxic effects at concentrations near the trypanocidal IC50, being considered a good starting point for the development of new anti-Chagas drug candidates.

Synthesis of Di- and Tri-Substituted Imidazole-4-carboxylates via PBu3-Mediated [3 + 2] Cycloaddition

Some new di- and trisubstituted imidazole-4-carboxylates were prepared from amidoacetic acids 3 in the present report. The key step to establish such imidazole-4-carboxylates stemmed from the PBu3-mediated [3 + 2] cycloaddition between in situ–generated Δ2-oxazolinone 4 and ethyl cyanoformate6. Our results indicated that trisubstituted imidazoles 7–20 were afforded in better yields than those of disubstituted imidazoles 21–27. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file.

ChemInform Abstract: Indium Trifluoride: A Highly Efficient Catalyst for the Synthesis of Fluorine‐Containing 2,4,5‐Trisubstituted Imidazoles under Solvent‐Free Conditions.

AbstractA novel and improved method for the synthesis of fluorine containing trisubstituted imidazoles (III) (16 examples) using an InF3‐catalyzed one‐pot, three‐component reaction is developed.

Synthesis and biological evaluation of di- and tri-substituted imidazoles as safer anti-inflammatory-antifungal agents

PURPOSE:In view of the potential pharmacophoric nature of imidazole nucleus, two series of imidazole derivatives, 2,4-disubstituted-1 H-imidazoles (2a-m) and 1,2,4-trisubstituted-1 H-imidazoles (3a-m), were synthesized with an aim of obtaining dual acting compounds i.e., anti-inflammatory and antifungal agents.MATERIALS AND METHODS:The title compounds were synthesized from 4-methoxyphenyl glyoxal (1) following multistep synthesis, and their structures were established on the basis of modern analytical techniques (IR, NMR and MS). The synthesized imidazoles were tested for their in vivo anti-inflammatory activity. In addition to that, some compounds were also evaluated for their analgesic and ulcerogenic effects. The compounds were also evaluated for their in vitro antifungal activity.RESULTS:Di- and tri-substituted imidazole derivatives (2a-m and 3a-m) were successfully synthesized. In in vivo anti-inflammatory test, six compounds (2 h, 2 l, 3 g, 3 h, 3 l and 3 m) exhibited good anti-inflammatory activity (49.58 to 58.02% inhibition) with minimal GI irritation (severity index; 0.17 to 0.34). These compounds were also tested for their analgesic activity and showed appreciable protection (40.53 to 49.60% protection) against saline-induced writhing test. Indomethacin was used as standard drug for comparison. In antifungal test, two compounds (3 h and 3 l) displayed appreciable antifungal activity (MIC; 12.5 μg mL-1) against the fungal strains tested.CONCLUSION:Two compounds, 2-(4-nitrophenyl)-4-(4-methoxyphenyl)-1-phenyl-1H-imidazole (3 h) and 2,4-di-(4-methoxyphenyl)-1-phenyl-1H-imidazole (3 l), emerged as lead compounds having dual biological activities; good anti-inflammatory as well as antifungal effect with lesser GI irritation.

ChemInform Abstract: Facile and Rapid Synthesis of Polysubstituted Imidazoles by Employing Y(NO3)3·6H2O as Catalyst.

AbstractA wide range of trisubstituted imidazoles (III) is synthesized by the present new yttrium‐catalyzed one‐pot reaction of benzil (I), aldehydes (II), and ammonium acetate under solvent‐free conditions.

ChemInform Abstract: Catalytic Procedures for Multicomponent Synthesis of Imidazoles: Selectivity Control During the Competitive Formation of Tri‐ and Tetrasubstituted Imidazoles.

AbstractThe catalytic potential of different fluoroboric acid‐derived catalyst systems is investigated for the cyclocondensation reaction of α‐diketones (I), aldehydes (II) and ammonium salt to form trisubstituted imidazoles (III) as well as the four component reaction using an additional amine (V) to afford tetrasubstituted derivatives (VI).

Convenient Synthesis of Highly Substituted Imidazole Derivatives

A one-pot synthesis of the trisubstituted imidazole derivatives from α-acetoxy-α-chloro-β-keto-esters, aldehydes, and ammonium acetate has been developed.

Facile synthesis of trisubstituted imidazoles from 1,2-di(furan-2-yl)-2-oxoethyl carboxylates and their chemiluminescence

Abstract A facile synthesis of trisubstituted imidazoles containing furan rings was reported. Imidazoles were produced from 1,2-di(furan-2-yl)-2-oxoethyl carboxylates over solid alumina as solid support impregnated with ammonium acetate under solvent-free microwave-assisted conditions. The method possessed many remarkable advantages, such as the short reaction time (5–10 min), affording moderate to excellent yields and saving resources, conveniently operating process, which provided an attractive and environmentally-friendly approach for the synthesis of the important heterocyclic compounds. Moreover, the chemiluminescence property of some compounds synthesized has been investigated.