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Substituted indole derivatives as antifungal agents: design, synthesis, in vitro and in silico evaluations

The Journal of Antibiotics volume 79, pages 93–109 (2026)Cite this article

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Abstract

Indole derivatives possess various biological activities, including antifungal, antibacterial, anticancer, antioxidant, antimalarial, antidiabetic, antitubercular, and anticholinesterase activities. This study focused on the synthesis of indole and its derivatives using the Fischer indole synthesis method and the Ullmann condensation reaction. The synthesized compound was characterized by melting point determination, UV-spectroscopy, thin layer chromatography, Fourier-transform infrared spectroscopy, and proton nuclear magnetic resonance. The zone of inhibition and the minimum Inhibitory concentration were used to determine antifungal activity against Candida albicans and Aspergillus niger. The parent molecule 2-methyl-1H-indole (B), with a yield of 44% was synthesized by Fischer indole synthesis and Ullmann condensation. Three derivatives of the parent molecules, 3-(2-methyl-1H-indol-1-yl)phenol (A1) with a yield of 68%, 1-(3-(2-methyl-1H-indol-1-yl)phenyl)ethan-1-one (A2) with a yield of 60%, and 2-methyl-1-(3-methylphenyl)-1H-indole (A3) with a yield of 84% were synthesized. Molecular docking revealed that all derivatives bound lanosterol 14α-demethylase more strongly than fluconazole (–7.1 kcal/mol), with A2 showing the highest affinity (–8.1 kcal/mol). (PDBID: 5TZ1). Furthermore, other computational studies through Pass analysis server, Drug likeness prediction by SwissADME, Toxicity prediction by Stoptox, and pkCSM server were performed on synthesized compounds to predict the biological activity. Collectively, these findings highlight indole derivatives, particularly A1 and A2, as promising antifungal leads with potent in vitro efficacy and strong molecular interactions with a clinically validated target.

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Acknowledgements

This research was supported by a National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (Grant no.: RS-2022-NR070862) and the “Regional Innovation System & Education” Project, funded by the Ministry of Education and the National Research Foundation of Korea. We also acknowledge the contributions of colleagues who assisted during this work.

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Author notes

  1. These authors contributed equally: Ashish Lamsal, Ashok Maurya.

Authors and Affiliations

  1. Department of Pharmacy, Universal College of Medical Science, Bhairahawa, Nepal

    Ashish Lamsal, Ashok Maurya, Shankar Thapa, Santosh Prasad Chaudhary Kurmi, Sharvendranath Maurya & Sushil Kumar Chaudhary

  2. College of Pharmacy, Mokpo National University, Muan, Republic of Korea

    Ashish Lamsal & Nam Ah Kim

  3. Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Biomedical and Healthcare Research Institute, Mokpo National University, Muan, Republic of Korea

    Ashish Lamsal & Nam Ah Kim

  4. Department of Medicinal Chemistry, University of Kansas, Lawrence, KS, USA

    Shankar Thapa

  5. Natural Product Chemistry, Pokhara University, Pokhara, Nepal

    Sharvendranath Maurya

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  1. Ashish Lamsal
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Contributions

Conceptualization, investigation: Ashok Maurya, BS. Methodology, writing original draft: Ashish Lamsal, MS, PhD fellow. Data curation, Writing, Review & Editing: Nam Ah Kim, PhD. Visualization: Shankar Thapa, MS. Methodology (microbiology): Sushil Kumar Chaudhary, MS. Formal analysis: Santosh Prasad Chaudhary Kurmi, BS, and Sharvendranath Maurya, BS.

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Correspondence to Nam Ah Kim.

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Lamsal, A., Maurya, A., Thapa, S. et al. Substituted indole derivatives as antifungal agents: design, synthesis, in vitro and in silico evaluations. J Antibiot 79, 93–109 (2026). https://doi.org/10.1038/s41429-025-00889-6

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