Preparation and antimicrobial activity of Mono-, Bis, and Tris-4,9-Dihydroxy-7,7-Dimethyl-5-(mono-substituted-aryl)-Hexahydro-Indeno[1,2-b]Indole-9,10-Dione derivatives.

In this study, indeno[1,2-b]indolone scaffolds were assembled through an operationally simple, aqueous Cu(OAc)₂ catalyzed three-component domino reaction furnishing mono-, bis- and tris-analogues in 68-95% isolated yields under mild conditions (60-85 °C, ≤ 150 min). Antimicrobial profiling (MIC & IC₅₀, 125 µg disc) against six clinically relevant strains revealed a steep electronic gradient: electron-withdrawing (EW) substituents usually drive sub-μg mL⁻¹ potency, whereas electron-donating (ED) groups abolish activity (>100 μg mL⁻¹). The meta-chloro mono-derivative 19g reaches 0.06 μg mL⁻¹ against (Bacillus subtilis) B. subtilis and (Escherichia coli) E. coli (equipotent to gentamicin, 2-fold above ampicillin), while the tris-expanded 23 breaches 0.015 μg mL⁻¹ 9-fold superior to ampicillin and the first indeno-indolone to match reference antibiotics without surpassing them. Mechanistic cues (ROS burst & DNA-gyrase docking) support a dual-mode action: membrane disruption plus topoisomerase inhibition. The scalable, metal-light protocol and clear EW > push-pull > ED ranking offer immediate lead-optimization handles to close the remaining 4-8-fold fungal gap versus Amphotericin B and to attenuate Gram-negative efflux, positioning 23 as a credible next-generation antibiotic candidate.