Strategic synthesis, antibacterial evaluation and SAR analysis of bisindole-chromone hybrids as an...

Antimicrobial resistance has diminished the effectiveness of existing antibiotics, necessitating the development of novel antibacterial agents. Herein, a focused library of twenty halogenated bisindole-chromone hybrids was designed through scaffold-hopping approaches and synthesized by a molecular hybridization technique via an efficient iodine-mediated coupling protocol. Antibacterial evaluation identified thirteen hybrids with potent anti-staphylococcal behaviour and favorable safety profiles toward mammalian cells and RBCs. Structure-activity relationship studies revealed that fluorine substitution on both chromone and bisindole fragments enhanced antibacterial potency, and identified BIC-12 as the optimal lead compound. BIC-12 exhibited MIC values of (1.5 μM/0.4 μg mL^-1) and (6.2 μM/2.0 μg mL^-1) against MSSA and MRSA, respectively, with rapid bactericidal activity and excellent antibiofilm efficacy. Mechanistic investigations revealed mild membrane perturbation together with pronounced cellular deformation and morphological alterations. These findings suggest that BIC-12 acts through a mechanism distinct from direct membrane disruption, although the precise molecular target remains to be elucidated. These findings identify fluorinated analogue BIC-12 as a promising in vitro anti-staphylococcal hit for further lead optimization and mechanistic investigation.