The Intestinal Barrier Protective Effect of Indole Aldehyde Derivatives on Acute Toxoplasma gondii Infection

Toxoplasmosis, a zoonotic infection caused by <i>Toxoplasma gondii</i> (<i>T. gondii</i>), poses a significant risk to human health and public safety. Despite the availability of clinical treatments, none effectively mitigate the intestinal barrier damage, which is the primary defense against <i>T. gondii</i> invasion. This study introduced aldehyde groups into the indole scaffold of a peptide-like structure to investigate the protective effects of these indole aldehyde derivatives on the intestinal barrier in mice with acute <i>T. gondii</i> infection. This approach leveraged the propensity of peptides and aldehyde groups to form hydrogen bonds. We synthesized a range of indole derivatives using the Vilsmeier-Haack reaction and evaluated their intestinal barrier protective effects both in vitro and in vivo. Our findings revealed that indole derivatives <b>A1</b> (1-Formyl-1<i>H</i>-indole-3-acetonitrile), <b>A3</b> (Indole-3-carboxaldehyde), <b>A5</b> (2-Chloro-1<i>H</i>-indole-3-carboxaldehyde), <b>A8</b> (1-Methyl-indole-3-carboxaldehyde), and <b>A9</b> (1-Methyl-2-phenyl-1<i>H</i>-indole-3-carboxaldehyde) demonstrated a higher selectivity index compared to the positive control, spiramycin. These derivatives enhanced gastrointestinal motility, increased glutathione (GSH) levels in the small intestine, and reduced malondialdehyde (MDA) and nitric oxide (NO) levels in the small intestine tissue and diamine oxidase (DAO) and NO levels in the serum of infected mice. Notably, <b>A3</b> exhibited comparable anti-<i>T. gondii</i> tachyzoites activity in the peritoneal cavity. Molecular docking studies indicated that the aldehyde group on the indole scaffold not only formed a hydrogen bond with NTPase-II but also interacted with TgCDPK1 through hydrogen bonding. Among the derivatives, <b>A3</b> showed promising intestinal barrier protective effects in mice with acute <i>T. gondii</i> infection. This research suggests that indole derivatives could serve as a potential therapeutic strategy for intestinal diseases induced by <i>T. gondii,</i> offering a novel direction for treating intestinal barrier damage and providing valuable insights for the chemical modification of drugs targeting <i>T. gondii</i>. Furthermore, it contributes to the advancement of therapeutic approaches for toxoplasmosis.