*Communication* **Synthesis, Molecular Docking and Antiplasmodial Activities of New Tetrahydro-**β**-Carbolines**

**Anna Jaromin 1,\* , Beata Gryzło <sup>2</sup> , Marek Jamrozik <sup>2</sup> , Silvia Parapini <sup>3</sup> , Nicoletta Basilico <sup>4</sup> , Marek Cegła <sup>2</sup> , Donatella Taramelli <sup>5</sup> and Agnieszka Zagórska 2,\***


**Abstract:** Malaria is still one of the most dangerous infectious diseases and the emergence of drug resistant parasites only worsens the situation. A series of new tetrahydro-β-carbolines were designed, synthesized by the Pictet–Spengler reaction, and characterized. Further, the compounds were screened for their in vitro antiplasmodial activity against chloroquine-sensitive (D10) and chloroquine-resistant (W2) strains of *Plasmodium falciparum*. Moreover, molecular modeling studies were performed to assess the potential action of the designed molecules and toxicity assays were conducted on the human microvascular endothelial (HMEC-1) cell line and human red blood cells. Our studies identified *N*-(3,3-dimethylbutyl)-1-octyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indole-3 carboxamide (**7**) (a mixture of diastereomers) as the most promising compound endowed with the highest antiplasmodial activity, highest selectivity, and lack of cytotoxicity. In silico simulations carried out for (1*S*,3*R*)-**7** provided useful insights into its possible interactions with enzymes essential for parasite metabolism. Further studies are underway to develop the optimal nanosized lipid-based delivery system for this compound and to determine its precise mechanism of action.

**Keywords:** tetrahydro-β-carbolines; *Plasmodium falciparum* (*P. falciparum*); antimalarial; antiparasitic agents; cytotoxicity; hemolysis; molecular docking
