Synthesis of 1,2,3-Triazole Derivatives of N,N-Dimethyltryptamine Isolated From Mimosa tenuiflora Root Bark: Antiplasmodial Activity In Silico and In Vitro.

Abstract

Malaria is a severe parasitic disease, with Plasmodium falciparum as one of the main etiological agents. The growing resistance to antimalarial drugs underscores the urgent need for the development of new therapeutic agents. This study describes the semisynthesis of eight new 1,4-disubstituted 1,2,3-triazole derivatives (3-10) from N,N-dimethyltryptamine (1), isolated from Mimosa tenuiflora. The derivatives were obtained through copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) reactions and characterized by NMR and mass spectrometry. Compound 1 showed low in vitro activity against the W2 strain of P. falciparum (IC₅₀ = 288.4 ± 28.53 µM), whereas compound 4 demonstrated promising activity (IC₅₀ = 4.8 ± 0.32 µM), with higher selectivity toward the TOV-21G cell line. In in silico studies, all derivatives showed more favorable binding energy values compared to compound 1, particularly compound 7 (-9.8 kcal/mol) relative to the crystallographic ligand (-6.9 kcal/mol). These results highlight the importance of structural modifications in the development of new antimalarial agents.