| Summary: | Rhizospheric fungi of medicinal plants are important sources for discovering novel and valuable secondary metabolites with potential pharmaceutical applications. In our research, five new dichlororesorcinols (<b>1–5</b>) and five known metabolites (<b>6–10</b>) were separated from the secondary metabolites of <i>Chaetomium</i> sp. SYP-F6997, which was isolated from the rhizospheric soil of <i>Panax notoginseng</i>. The identification of these compounds was confirmed using various spectroscopic techniques including ESI-MS, UV, IR, NMR and ECD analyses. These findings highlight the potential of rhizospheric fungi as a rich source of novel bioactive compounds. In addition, chiral HPLC was used to successfully separate the enantiomers compound <b>4</b> and compound <b>5</b>, and TDDFT-ECD/optical rotation calculations were used to test their absolute configurations. This is the first report of compounds <b>1–10</b> from the genus <i>Chaetomium</i>, and the first report of compounds <b>1–5</b> and <b>7</b> from the family <i>Chaetomiaceae</i>. We proposed plausible biosynthetic pathways for dichlororesorcinols <b>1–6</b> based on their analogous carbon skeleton. These findings provide insights into the biosynthesis of these compounds and expand our understanding of the secondary metabolites produced by <i>Chaetomium</i> sp. SYP-F6997. To evaluate their potential as therapeutic agents, we investigated the cytotoxic activity of all the isolated metabolites against cell lines H9, HL-60, K562, THP-1 and CEM using the MTT method. The new compounds <b>1</b> and <b>2</b> exhibited significant cytotoxic activities against H9 and CEM, with IC50 values lower than 10 µM. To further explore the potential mechanisms of action, we performed molecular docking studies to investigate the interactions between compounds <b>1</b> and <b>2</b> with the potential target ERK2. Our results demonstrate that the compounds exhibited strong binding abilities and formed H-bond interactions with ERK2, providing support for their potent antitumor activities and promising potential as lead molecules for the development of antitumor therapeutics.
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