Lowe, RA, Taylor, D, Chibale, K et al. (2 more authors) (2020) Synthesis and Evaluation of the Performance of a Small Molecule Library Based on Diverse Tropane-Related Scaffolds. Bioorganic & Medicinal Chemistry, 28 (9). 115442. ISSN 0968-0896
Abstract
A unified synthetic approach was developed that enabled the synthesis of diverse tropane-related scaffolds. The key intermediates that were exploited were cycloadducts formed by reaction between 3-hydroxy-pyridinium salts and vinyl sulfones or sulfonamides. The diverse tropane-related scaffolds were formed by addition of substituents to, cyclisation reactions of, and fusion of additional ring(s) to the key bicyclic intermediates. A set of 53 screening compounds was designed, synthesised and evaluated in order to determine the biological relevance of the scaffolds accessible using the synthetic approach. Two inhibitors of Hedgehog signalling, and four compounds with weak activity against the parasite P. falciparum, were discovered. Three of the active compounds may be considered to be indotropane or pyrrotropane pseudo natural products in which a tropane is fused with a fragment from another natural product class. It was concluded that the unified synthetic approach had yielded diverse scaffolds suitable for the design of performance-diverse screening libraries.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2020 Elsevier Ltd. All rights reserved. This is an author produced version of an article published in Bioorganic and Medicinal Chemistry. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | molecular diversitymolecular scaffoldsalkaloidsHedgehog signallingantimalarials |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) > Organic Chemistry (Leeds) |
Funding Information: | Funder Grant number EPSRC (Engineering and Physical Sciences Research Council) EP/N025652/1 |
Depositing User: | Symplectic Publications |
Date Deposited: | 18 Mar 2020 12:38 |
Last Modified: | 27 Jun 2022 12:25 |
Status: | Published |
Publisher: | Elsevier |
Identification Number: | 10.1016/j.bmc.2020.115442 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:158497 |