Design and synthesis of a library of C8-substituted sulfamidoadenosines to probe bacterial permeability Journal Article
| Authors: | Yildirim, O.; Barman, D.; Chung, M.; Stone, S.; Geißen, R.; Boby, M. L.; Sherborne, B. S.; Tan, D. S. |
| Article Title: | Design and synthesis of a library of C8-substituted sulfamidoadenosines to probe bacterial permeability |
| Abstract: | Gram-negative bacteria pose a major challenge in antibiotic drug discovery because their cell envelope presents a permeability barrier that affords high intrinsic resistance to small-molecule drugs. The identification of correlations between chemical structure and Gram-negative permeability would thus enable development of predictive tools to facilitate antibiotic discovery. Toward this end, have advanced a library design paradigm in which various chemical scaffolds are functionalized at different regioisomeric positions using a uniform reagent set. This design enables decoupling of scaffold, regiochemistry, and substituent effects upon Gram-negative permeability of these molecules. Building upon our recent synthesis of a library of C2-substituted sulfamidoadenosines, we have now developed an efficient synthetic route to an analogous library of regioisomeric C8-substituted congeners. The C8 library samples a region of antibiotic-relevant chemical space that is similar to that addressed by the C2 library, but distinct from that sampled by a library of analogously substituted oxazolidinones. Selected molecules were tested for accumulation in Escherichia coli in a pilot analysis, setting the stage for full comparative evaluation of these libraries in the future. © 2024 Elsevier Ltd |
| Keywords: | drug discovery; antibiotic resistance; gram-negative bacteria; diversity-oriented synthesis; nucleoside analogue |
| Journal Title: | Bioorganic & Medicinal Chemistry Letters |
| Volume: | 110 |
| ISSN: | 0960-894X |
| Publisher: | Pergamon-Elsevier Science Ltd |
| Date Published: | 2024-09-15 |
| Start Page: | 129844 |
| Language: | English |
| DOI: | 10.1016/j.bmcl.2024.129844 |
| PUBMED: | 38851357 |
| PROVIDER: | scopus |
| PMCID: | PMC11361631 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding authors is MSK author: Derek S. Tan -- Source: Scopus |
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