One-Pot Synthesis and Anticancer Activity Evaluation of Indolo[1,2-a]quinoline-7-carbonitrile Derivatives

Indolo[1,2-a]quinoline derivatives represent an attractive heterocyclic scaffold in anticancer drug discovery. Herein, fifty-four novel indolo[1,2-a]quinoline-7-carbonitrile analogs were synthesized via a transition-metal-free cascade reaction involving nucleophilic aromatic substitution and Knoevenagel condensation, affording yields up to 87%. All compounds were evaluated for their antiproliferative activities against human colorectal (HCT-116 and HT-29) and breast (MCF-7) cancer cell lines using the MTT assay. Eleven analogs exhibited high potency with IC₅₀ values ranging from 2.16 to 8.18 µM. Notably, 2-bromoindolo[1,2-a]quinoline-7-carbonitrile displayed broad-spectrum cytotoxicity across HCT-116, HT-29, and MCF-7 lines (IC₅₀ = 3.64 ± 0.72, 5.29 ± 1.83, and 6.06 ± 0.16 µM, respectively). To explore potential binding modes and rationalize structural features, molecular docking simulations were conducted against CDK2, CDK6, and EGFR kinase models. The in silico results revealed strong predicted binding affinities (-7.73 to -9.49 kcal/mol), driven predominantly by C7-cyano hydrogen bonding and hydrophobic interactions, providing hypothetical insights into how these scaffolds might interact with ATP-binding pockets. These findings demonstrate that the indolo[1,2-a]quinoline-7-carbonitrile framework holds significant promise as a pharmacophore for further mechanistic and drug development studies.