Development of biscoumarin compounds with quorum-quenching potential: Synthetic, biological, and in silico studies

Abstract

Coumarins are well known for their biological properties. A mild, efficient synthetic route is developed for biscoumarin compounds using ceric ammonium nitrate at room temperature. This method has broad substrate tolerance with 70 percent-97 percent isolated yield. The method also exemplified industrial utility as tested on a multigram scale, and particularly avoided column chromatography. Biscoumarin compounds prepared with diverse substitutions were screened for their quorum-quenching (QQ) potential to serve as potential alternatives to antibiotics against pathogenic bacteria. QQ activity of the prepared compounds was determined by their ability to inhibit violacein pigment production of bioreporter Chromobacterium violaceum in a concentration-dependent manner. Biscoumarins (1g, 1n, and 1d) showed impressive QQ activity on C. violaceum and also revealed very good antibiofilm activity against gram-negative (Pseudomonas aeruginosa ATCC 27853 and Salmonella typhimurium ATCC 14028) and gram-positive (Staphylococcus aureus ATCC 6538) human pathogens via the QQ mechanism, indicating their versatile nature against diverse QS signaling systems (AHL, HAQs, and agr). Moreover, molecular docking studies further confirmed our results with impressive binding affinity -8.7, -8.5, and -8.4 kcal/mol (1n, 1g, and 1d) to protein MvfR (PqsR) and binding affinity -9 kcal/mol to protein AgrA (transcription factor), both controlling the expression of virulence factors in P. aeruginosa and S. aureus, respectively. The present investigation highlights the potential of biscoumarin compounds in the medical field to treat life-threatening infections as an alternative to antibiotics.