Synthesis, biological evaluation, molecular docking, molecular dynamics simulation, and ADME studies of novel carbazole-aniline hybrids as cytotoxic agents.

Abstract

A novel series of seven carbazole-aniline hybrids (5a-5 g) were designed, synthesized, and evaluated as potential anticancer agents. Among them, compound 5e, bearing a para-methoxy substituent, emerged as the most potent candidate, demonstrating significant cytotoxicity against breast cancer (MCF-7) and colon cancer (SW480) cell lines with IC₅₀ values of 26.4 ± 2.54 µM and 34.5 ± 1.69 µM, respectively. Notably, its activity against MCF-7 was comparable to the reference drug Erlotinib (IC₅₀ = 39.3 µM). Structure-activity relationship studies revealed that electron-donating groups significantly enhance cytotoxic effects, while electron-withdrawing substitutions diminish activity. Molecular docking studies showed that compound 5e binds effectively to the EGFR active site with a binding energy of -8.6 kcal/mol, forming key hydrogen bonds with critical residues Asp831 and Thr766. Molecular dynamics simulations further confirmed the stability of the 5e-EGFR complex. In silico ADME predictions indicated favorable drug-like properties for all compounds, consistent with Lipinski's Rule of Five. Based on its potent cytotoxicity, strong target binding, and optimal pharmacokinetic profile, compound 5e is identified as a promising lead candidate for further development as an EGFR-targeting anticancer agent.

AI evidence extraction

Main findings

Seven carbazole-aniline hybrids (5a–5g) were synthesized and evaluated for cytotoxicity; compound 5e showed the strongest activity with IC50 26.4 ± 2.54 µM (MCF-7) and 34.5 ± 1.69 µM (SW480), with MCF-7 activity comparable to erlotinib (IC50 39.3 µM). Docking indicated 5e binds the EGFR active site (binding energy −8.6 kcal/mol) with hydrogen bonds to Asp831 and Thr766, and molecular dynamics suggested a stable 5e–EGFR complex; ADME predictions were favorable for all compounds and consistent with Lipinski’s Rule of Five.

Outcomes measured

• Cytotoxicity (IC50) in MCF-7 breast cancer cell line
• Cytotoxicity (IC50) in SW480 colon cancer cell line
• EGFR binding energy (molecular docking)
• Stability of 5e–EGFR complex (molecular dynamics simulation)
• In silico ADME / drug-likeness (Lipinski Rule of Five)

{
    "study_type": "in_vitro",
    "exposure": {
        "band": null,
        "source": null,
        "frequency_mhz": null,
        "sar_wkg": null,
        "duration": null
    },
    "population": null,
    "sample_size": null,
    "outcomes": [
        "Cytotoxicity (IC50) in MCF-7 breast cancer cell line",
        "Cytotoxicity (IC50) in SW480 colon cancer cell line",
        "EGFR binding energy (molecular docking)",
        "Stability of 5e–EGFR complex (molecular dynamics simulation)",
        "In silico ADME / drug-likeness (Lipinski Rule of Five)"
    ],
    "main_findings": "Seven carbazole-aniline hybrids (5a–5g) were synthesized and evaluated for cytotoxicity; compound 5e showed the strongest activity with IC50 26.4 ± 2.54 µM (MCF-7) and 34.5 ± 1.69 µM (SW480), with MCF-7 activity comparable to erlotinib (IC50 39.3 µM). Docking indicated 5e binds the EGFR active site (binding energy −8.6 kcal/mol) with hydrogen bonds to Asp831 and Thr766, and molecular dynamics suggested a stable 5e–EGFR complex; ADME predictions were favorable for all compounds and consistent with Lipinski’s Rule of Five.",
    "effect_direction": "benefit",
    "limitations": [],
    "evidence_strength": "low",
    "confidence": 0.7399999999999999911182158029987476766109466552734375,
    "peer_reviewed_likely": "yes",
    "keywords": [
        "carbazole-aniline hybrids",
        "cytotoxicity",
        "MCF-7",
        "SW480",
        "EGFR",
        "molecular docking",
        "molecular dynamics",
        "ADME",
        "Lipinski"
    ],
    "suggested_hubs": []
}

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