Antibacterial activity of structurally diverse natural prenylated isobavachalcone derivatives†

Isobavachalcone (IBC) is a natural prenylated flavonoid containing chalcone and prenyl chain moieties with a wide range of biological and pharmacological properties. In this work, we synthesized structurally diversified derivatives (IBC-2 to IBC-10) from the natural prenylated chalcone IBC isolated from Psoralea corylifolia and assessed their antibacterial potency against the Gram-positive and Gram-negative bacterial strains S. aureus ATCC 29213, MRSA ATCC 15187, E. coli ATCC25922 and P. aeruginosa ATCC 27853. IBC and IBC-2 exhibited a minimum inhibition concentration (MIC) of 5.0 μM against S. aureus ATCC 29213, whereas IBC-3 exhibited a broad-spectrum activity against Gram-positive and Gram-negative pathogens. Cytotoxicity assessments on the murine RAW 264.7 macrophage cell line revealed minimal to moderate cytotoxicity for IBC-2 and IBC-3 with a favorable selectivity index (>10). Time- and concentration-dependent studies further supported the bactericidal nature of the compounds, as IBC, IBC-2, and IBC-3 exhibited concentration-dependent killing of S. aureus in a time-dependent manner. Furthermore, combination studies, SEM analysis, and PI staining suggest that IBC-3's mechanism of action targets the bacteria's cytoplasmic membrane or cell wall. The bioactive compounds displayed promising drug-like characteristics and a favorable pharmacokinetic profile (ADME-Tox), indicating a projected high oral bioavailability. Structure–activity relationships (SARs) drawn from this study reveal that a prenyl chain at the A-ring and hydroxy functional groups attached to the aromatic rings of chalcone scaffolds are responsible for this antibacterial potential, which will be helpful in the future discovery and development of antibiotics from natural products to overcome the antibiotic resistance crisis.