Abstract
Figure Presented. The Pseudomonas aeruginosa quorum-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. aeruginosa reporter assay, systematic modification of 1 allowed 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 1 with functions containing heteroatoms, especially an NH group. This modification can be combined with replacement of the homoserine lactone system in 1 with stable cyclic groups. For example, we found the simple compound N1-(5-chloro-2-hydroxyphenyl)-N 3-octylmalonamide (25d) to be over twice as potent as 1 as an immune suppressor while displaying LasR-induction antagonist activity.
Original language | English (US) |
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Pages (from-to) | 3348-3359 |
Number of pages | 12 |
Journal | Journal of Medicinal Chemistry |
Volume | 54 |
Issue number | 9 |
DOIs | |
State | Published - May 12 2011 |
Externally published | Yes |
All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Drug Discovery