Molecular docking and biological evaluation of novel urea-tailed mannich base against Pseudomonas aeruginosa. (May 2019) - Mohanvel, Sucharitha Kannappan
Abstract: Emergence of multi-drug resistant bacterial pathogens is escalating and it is essential to develop novel strategies to combat these super bugs. LasR is a regulator switch that plays a vital role in quorum sensing (QS) and pathogenesis of Pseudomonas aeruginosa. The present study reports two novel Mannich base (1-(phenyl ( o -tolylamino) methyl) urea and 3-((1H-Imidazole-1-yl) methylnaphthalene-2-ol with enhanced anti -QS and antibiofilm activities. Synthetic compound revealed prolific interaction patterns with LasR quorum sensing receptor and showed to exhibit LasR antagonistic activities in P. aeruginosa . In-vitro LasR-inhibitory activities were further confirmed by biofilm and pyocyanin inhibition assays which showed a dose-dependent activity. The Mannich base also repressed the mRNA transcripts levels of lasA and lasB genes, confirming its active role in LasR inhibitory activity. Importantly, C1 and C2 played a crucial role in antagonizing LasR receptor by forming H-bonds with Tyr 47 in the LasR active site and the presence of urea moiety on one of the Mannich base was a discrete advantage. Taken together, the insilico and invitro assays revealed similar evidences, thus confirming the mode of action of the Mannich bases. Overall the findings will assist in drug designing and for developing newer drugs with Mannich bases and its derivatives for treatment of P. aeruginosa. Highlights: Urea-tailed Mannich base (1-(phenyl ( o -tolylamino) methyl) urea (C1)) was synthesized and characterized. First report on antibiofilm and anti-quorum sensing activities of C1 and C2 against Pseudomonas aeruginosa. C1 exhibited LasR inhibitory activities and antagonistic activities. Structure activity relationship (SAR) studies revealed that urea moiety in C1 is vital for stabilizing the interaction with the LasR receptor. The study provides a starting point for deriving Mannich bases and its bioisosteres for use as quorum quenching agents.