Immunosuppressive but non-LasR-inducing analogues of the pseudomonas aeruginosa quorum-sensing molecule N-(3-Oxododecanoyl)-l-homoserine Lactone

Gopal P. Jadhav, Siri Ram Chhabra, Gary Telford, Doreen S.W. Hooi, Karima Righetti, Paul Williams, Barrie Kellam, David I. Pritchard, Peter M. Fischer

Research output: Contribution to journalArticle

16 Scopus citations

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 languageEnglish (US)
Pages (from-to)3348-3359
Number of pages12
JournalJournal of Medicinal Chemistry
Volume54
Issue number9
DOIs
StatePublished - May 12 2011
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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    Jadhav, G. P., Chhabra, S. R., Telford, G., Hooi, D. S. W., Righetti, K., Williams, P., Kellam, B., Pritchard, D. I., & Fischer, P. M. (2011). Immunosuppressive but non-LasR-inducing analogues of the pseudomonas aeruginosa quorum-sensing molecule N-(3-Oxododecanoyl)-l-homoserine Lactone. Journal of Medicinal Chemistry, 54(9), 3348-3359. https://doi.org/10.1021/jm2001019