Search for Pseudomonas aeruginosa immune-modulatory but non-inducing agents

Dysfunctional immunity which is the most common antecedent of immunological diseases is central to the common disorders like rheumatoid arthritis, psoriasis, thyroid disease, type-1 diabetes mellitus, multiple sclerosis and other autoimmune conditions that are leading causes of chronic morbidities and disabilities. The currently employed therapies suffer from serious side effects. For example, steroid therapy, being nonselective is seldom used. Myleotoxicity limits azathioprine while cyclosporine-A (CsA) and FK506 do show myleo-, nephro and neuro-toxicities. Antibody therapies cause immune mediated toxicity. Therefore, the need of developing less toxic and specific immune modulatory agents is a top priority. Recently, Pseudomonas aeruginosa quorum sensing signal molecules (QSSMs), N-(3-oxododecanoyl)-L-homoserine lactone (3O, C12-HSL) and 2-n-heptyl-3-hydroxy-4-(1H)-quinolone (PQS) have been found to modulate eukaryotic immune processes via different targets. The structure activity relationship (SAR) study of 3O, C12-HSL by Chhabra et.al, showed that L-homoserine lactone ring, 3-oxo or hydroxyl group and 12 to14-carbons long acyl chain, apparently conferring optimum lipophilicity and flexibility, are important for immune modulation. However, the new analogues including 3O, C12-HSL negated clinical usefulness as these also participated in bacterial quorum-sensing (QS) activity thus promoting bacterial growth. Also analogues with more than 12-carbons alkyl chain could not be explored by in vitro immune assays due to their limited solubility in the solvents employed. The present study addresses these issues by making further judicial structural changes in the 3O, C12-HSL in order to optimize its immune modulatory activity while losing its intrinsic QS activity. Accordingly, a series of new ring variants, 3-acetoxy, aza, thia, oxa and fluorine substituted analogues were developed. The later were largely confined in the 1, 3-dicarbonyl segment of the 3O, C12-HSL structur