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Lead optimization of 3-indoleacetonitrile identifies candidate compounds with improved anti-influenza activity and safety profiles
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DOI：10.3389/fmicb.2026.1904663.png)
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Abstract
En 中文
IntroductionInfluenza A virus (IAV) remains a major respiratory pathogen that causes substantial morbidity; mortality; and socioeconomic burden worldwide. Although several antiviral agents are available for clinical use; their effectiveness is often compromised by the emergence of drug-resistant variants; limited therapeutic windows; and potential adverse effects. Small-molecule antivirals represent an important strategy for influenza treatment; however; improving antiviral efficacy while minimizing toxicity remains a major challenge in drug development. In this study; we sought to identify candidate low-toxicity derivatives structurally related to 3-indoleacetonitrile; a previously characterized compound with anti-influenza activity.MethodsCandidate compounds were selected through a computational screening strategy integrating structural similarity analysis; toxicity prediction; and drug-likeness assessment. Cytotoxicity was evaluated by CCK-8 assays and morphological observation in A549 cells. Antiviral activity was assessed using a recombinant luciferase-expressing PR8 influenza virus. Promising candidates were subsequently evaluated in a lethal influenza mouse model challenged with 10 × LD50 PR8 virus. Body weight changes; survival rates; lung pathology; viral burden; and serum AST/ALT levels were analyzed to determine antiviral efficacy and safety in vivo.ResultsFour candidates—Indole-3-ethanol; Indole-3-acetamide; 3-Indoleacetic acid; and Acetohydroxamic acid—were identified. Cytotoxicity analyses revealed that Indole-3-ethanol and Indole-3-acetamide exhibited substantially lower toxicity than the parent compound 3-indoleacetonitrile; maintaining high cell viability at concentrations exceeding 640 μM. Morphological examination further confirmed their improved safety profiles. In antiviral assays; Indole-3-ethanol and Indole-3-acetamide demonstrated potent inhibition of IAV replication; while 3-Indoleacetic acid and Acetohydroxamic acid showed little or no detectable antiviral activity. In vivo; Indole-3-ethanol treatment alleviated body weight loss; delayed mortality; reduced pulmonary pathological injury; and significantly decreased viral loads in the lungs of PR8-infected mice. In addition; AST/ALT analysis indicated lower toxicity of Indole-3-ethanol and Indole-3-acetamide compared with 3-indoleacetonitrile.ConclusionStructural optimization of the lead compound 3-indoleacetonitrile led to the identification of derivatives with improved antiviral activity and reduced toxicity. Among the compounds evaluated; Indole-3-ethanol exhibited the most favorable balance between efficacy and safety; demonstrating potent anti-influenza activity in both cell-based and animal models. These findings support the utility of computationally guided lead optimization and identify Indole-3-ethanol as a promising candidate for further development as an anti-influenza therapeutic.
Keywords:
influenza A virus
antiviral therapy
small-molecule antivirals
indole derivatives
3-indoleacetonitrile
indole-3-ethanol
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