| Autor: |
Jadhav, Gopal P., Chhabra, Siri Ram, Telford, Gary, Hooi, Doreen S. W., Righetti, Karima, Williams, Paul, Kellam, Barrie, Pritchard, David I., Fischer, Peter M. |
| Zdroj: |
Journal of Medicinal Chemistry; 20240101, Issue: Preprints |
| Abstrakt: |
The Pseudomonas aeruginosaquorum-sensing molecule N-(3-oxododecanoyl)-l-homoserine lactone (1) is involved not only in bacterial activation but also in subversion of the host immune system, and this compound might thus be used as a template to design immunosuppressive agents, provided derivatives devoid of quorum-sensing activity could be discovered. By use of a leukocyte proliferation assay and a newly developed bioluminescent P. aeruginosareporter assay, systematic modification of 1allowed us to delineate the bacterial LasR-induction and host immunosuppressive activities. The main determinant is replacement of the methylene group proximal to the β-ketoamide in the acyl chain of 1with functions containing heteroatoms, especially an NH group. This modification can be combined with replacement of the homoserine lactone system in 1with stable cyclic groups. For example, we found the simple compound N1-(5-chloro-2-hydroxyphenyl)-N3-octylmalonamide (25d) to be over twice as potent as 1as an immune suppressor while displaying LasR-induction antagonist activity. |
| Databáze: |
Supplemental Index |
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