Guanidine hydrochloride catalyzed alternative synthesis of xanthenediones with broad spectrum quorum quenching activity

Abstract

Xanthenediones are fused oxygen heterocycles with diverse biological properties. We herein report an efficient method for preparation of xanthenediones using aldehydes and diones with guanidine hydrochloride. This methodology demonstrated tolerance to diverse substitution on reactants giving products in good yields. In the present investigation, Thirty one xanthenedione derivatives were synthesised including eight new derivatives and screened for their potential to inhibit violacein and prodigiosin pigments synthesis in bioreporter bacteria Chromobacterium violaceum and Serratia marcescens respectively regulated by QS systems (CviI/R, and smaI/R). Four xanthenedione derivatives (4, 5, 30, 31) showed very promising Quorum quenching (QQ) activity by inhibiting QS regulated pigments (violacein and prodigiosin) production. When tested against clinical isolate Pseudomonas aeruginosa, xanthenedione derivatives showed significant reduction in biofilm formation, swarming motility, Pyocyanin and Rhamnolipid production controlled by Las and Pqs QS systems in dose dependent manner. Moreover, molecular docking studies supported our results with good binding affinity of -7.24, -7.83, -7.38 and -7.6 kcal/mol respectively to protein 4JVC (multiple virulence factor regulator MvfR/PqsR of Pqs QS system) of Pseudomonas aeruginosa. The present investigation highlights potential of xanthenediones to disrupt multiple QS systems (CviI/R, smaI/R, LasI/R and Pqs) and its suitability as drug to control MDR bacterial infections.