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

School of Pharmacy, University of Nottingham, University Park, Nottingham, NG7 2RD, U.K.

Journal of medicinal chemistry 2011 May 12

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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 N(1)-(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.

Citation

Gopal P Jadhav, Siri Ram Chhabra, Gary Telford, Doreen S W Hooi, Karima Righetti, Paul Williams, Barrie Kellam, David I Pritchard, Peter M Fischer. Immunosuppressive but non-LasR-inducing analogues of the Pseudomonas aeruginosa quorum-sensing molecule N-(3-oxododecanoyl)-l-homoserine lactone. Journal of medicinal chemistry. 2011 May 12;54(9):3348-59