Design, Synthesis, Spectral Characterization of 2,3-Benzopyrrole Derivatives as Potential Anti-Breast Cancer Agents — an in silico-based approach

Abstract

Background: Indole-based 2,3-benzopyrrole derivatives show varied pharmacological effects, yet their activity against breast cancer targets such as estrogen receptor (ER) and epidermal growth factor receptor (EGFR) is underexplored. This study aimed to design, synthesize, characterize, and evaluate novel 2,3-benzopyrrole Schiff-base derivatives for anti-inflammatory and anti-breast cancer potential using in vitro, in vivo, and in silico methods. Methods: A series of eight compounds (PD1–PD5, SB4, SB6, SB7) were synthesized via chalcone and Schiff-base routes from indole-3-carbaldehyde and characterized by FT-IR, 1H NMR, and mass spectrometry. Molecular docking was performed with MOE against ER (PDB: 4XI3) and EGFR (PDB: 1M17), and pre-ADMET profiling assessed drug-likeness. In vitro anti-inflammatory activity used the egg-albumin denaturation assay (100–500 μg/mL) and in vivo efficacy was tested in carrageenan-induced paw edema in Wistar rats (40 mg/kg). Results: Spectral data confirmed the structures and yields were satisfactory for the target compounds. Docking revealed notable binding affinities: PD2, PD3, and PD5 showed strong interactions with EGFR (best: PD2 −10.05 kcal·mol−1) and PD1, PD2, PD5 with ER (best: PD5 −10.10 kcal·mol−1), with favorable key residue contacts. Pre-ADMET predicted good gastrointestinal absorption, acceptable lipophilicity, and generally low toxicity for most compounds. In vitro, PD2, PD3, and PD5 demonstrated significant protein-denaturation inhibition at 500 μg/mL (≈76–77%), comparable to aceclofenac. In vivo, PD2 and PD5 produced marked reductions in paw edema (inhibition ≈35.8% and 30.4%, respectively) versus diclofenac (≈42.2%). Conclusion: Novel 2,3-benzopyrrole indole Schiff-base derivatives, particularly PD2 and PD5, exhibit promising anti-inflammatory activity and strong in silico affinity to ER and EGFR, supporting their potential as lead candidates for further cytotoxic and mechanistic evaluation in breast cancer drug development. Key next steps include cell-based cytotoxicity assays and mechanistic studies.