Modular Synthesis of
Di- and Trisubstituted Imidazoles
from Ketones and Aldehydes: A Route to Kinase Inhibitors

de Toledo, Ian; Grigolo, Thiago A.; Bennett, James M; Elkins, Jonathan M; Pilli, Ronaldo A.

doi:10.1021/acs.joc.9b01844

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Modular Synthesis of Di- and Trisubstituted Imidazoles from Ketones and Aldehydes: A Route to Kinase Inhibitors

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Author(s): Ian de Toledo ^† , Thiago A. Grigolo ^† , James M. Bennett ^‡ , Jonathan M. Elkins ^‡ ^, ^§ , Ronaldo A. Pilli ^† ^,

Publication date (Electronic): 28 August 2019

Journal: The Journal of Organic Chemistry

Publisher: American Chemical Society

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Abstract

A one-pot and modular approach to the synthesis of 2,4(5)-disubstituted imidazoles was developed based on ketone oxidation, employing catalytic HBr and DMSO, followed by imidazole condensation with aldehydes. This methodology afforded twenty-nine disubstituted NH-imidazoles (23%–85% yield). A three-step synthesis of 20 kinase inhibitors was achieved by employing this oxidation–condensation protocol, followed by bromination and Suzuki coupling in the imidazole ring to yield trisubstituted NH-imidazoles (23%–69%, three steps). This approach was also employed in the synthesis of known inhibitor GSK3037619A.

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Comprehensive characterization of the Published Kinase Inhibitor Set.

Jonathan M. Elkins, Vita Fedele, Marta Szklarz … (2016)

Despite the success of protein kinase inhibitors as approved therapeutics, drug discovery has focused on a small subset of kinase targets. Here we provide a thorough characterization of the Published Kinase Inhibitor Set (PKIS), a set of 367 small-molecule ATP-competitive kinase inhibitors that was recently made freely available with the aim of expanding research in this field and as an experiment in open-source target validation. We screen the set in activity assays with 224 recombinant kinases and 24 G protein-coupled receptors and in cellular assays of cancer cell proliferation and angiogenesis. We identify chemical starting points for designing new chemical probes of orphan kinases and illustrate the utility of these leads by developing a selective inhibitor for the previously untargeted kinases LOK and SLK. Our cellular screens reveal compounds that modulate cancer cell growth and angiogenesis in vitro. These reagents and associated data illustrate an efficient way forward to increasing understanding of the historically untargeted kinome.

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Acidic Ionic Liquids.

Ananda Amarasekara (2016)

Ionic liquid with acidic properties is an important branch in the wide ionic liquid field and the aim of this article is to cover all aspects of these acidic ionic liquids, especially focusing on the developments in the last four years. The structural diversity and synthesis of acidic ionic liquids are discussed in the introduction sections of this review. In addition, an unambiguous classification system for various types of acidic ionic liquids is presented in the introduction. The physical properties including acidity, thermo-physical properties, ionic conductivity, spectroscopy, and computational studies on acidic ionic liquids are covered in the next sections. The final section provides a comprehensive review on applications of acidic ionic liquids in a wide array of fields including catalysis, CO2 fixation, ionogel, electrolyte, fuel-cell, membrane, biomass processing, biodiesel synthesis, desulfurization of gasoline/diesel, metal processing, and metal electrodeposition.

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Comprehensive review in current developments of imidazole-based medicinal chemistry.

Guri Damu, Rong-Xia Geng, Cheng-He Zhou … (2014)

Imidazole ring is an important five-membered aromatic heterocycle widely present in natural products and synthetic molecules. The unique structural feature of imidazole ring with desirable electron-rich characteristic is beneficial for imidazole derivatives to readily bind with a variety of enzymes and receptors in biological systems through diverse weak interactions, thereby exhibiting broad bioactivities. The related research and developments of imidazole-based medicinal chemistry have become a rapidly developing and increasingly active topic. Particularly, numerous imidazole-based compounds as clinical drugs have been extensively used in the clinic to treat various types of diseases with high therapeutic potency, which have shown the enormous development value. This work systematically gives a comprehensive review in current developments of imidazole-based compounds in the whole range of medicinal chemistry as anticancer, antifungal, antibacterial, antitubercular, anti-inflammatory, antineuropathic, antihypertensive, antihistaminic, antiparasitic, antiobesity, antiviral, and other medicinal agents, together with their potential applications in diagnostics and pathology. It is hoped that this review will be helpful for new thoughts in the quest for rational designs of more active and less toxic imidazole-based medicinal drugs, as well as more effective diagnostic agents and pathologic probes.

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Author and article information

Journal

Journal ID (nlm-ta): J Org Chem

Journal ID (iso-abbrev): J. Org. Chem

Journal ID (publisher-id): jo

Journal ID (coden): joceah

Title: The Journal of Organic Chemistry

Publisher: American Chemical Society

ISSN (Print): 0022-3263

ISSN (Electronic): 1520-6904

Publication date (Electronic): 28 August 2019

Publication date (Print): 01 November 2019

Volume: 84

Issue: 21

Pages: 14187-14201

Affiliations

[† ]Department of Organic Chemistry, Institute of Chemistry, University of Campinas, UNICAMP , Campinas, São Paulo 13083-970, Brazil

[‡ ]Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom

[§ ]Structural Genomics Consortium, Departamento de Genética e Evolução, Instituto de Biologia, UNICAMP , Campinas, São Paulo 13083-886, Brazil

Author notes

[* ]E-mail: rapilli@ 123456unicamp.br .

Article

DOI: 10.1021/acs.joc.9b01844

PMC ID: 6829625

PubMed ID: 31460764

SO-VID: e8af16a4-639f-473b-bcdd-39a48ba89245

License:

This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.