Phytochemical investigation of Chrysanthellum americanum Vatke and its constituents- a targeted approach for the treatment of leishmaniasis.

The present study is focused on the isolation and identification of new therapeutic candidates from Chrysanthellum americanum Vatke., and their efficacy against pteridine reductase-1 (PTR1), a valid chemotherapeutic target in the Leishmania parasite. Henceforth, a new compound, chrysanamerine (1), along with 7 known compounds, polyacetylene 2, and flavonoids 3-8, were isolated from C. americanum. Their structures were determined by chemical and spectroscopic analyses and compared with the reported spectroscopic data. All compounds were evaluated for their anti-leishmanial activity against PTR1 via biochemical mechanism-based assay. The in vitro results showed five potential hits including a new compound, chrysanamerine (1), and four known compounds against the PTR1 enzyme. Among them, compound 1 showed a potent enzyme inhibition with an IC 50 of 31.02 ± 2.36 μM, whereas a moderate inhibition was observed in cases of compounds 5 and 6 (IC 50  = 59.86 ± 3.32, and 45.32 ± 3.5 μM, respectively). Whereas, compounds 3 and 8 showed mild inhibition (IC 50  = 72.12 ± 1.12, and 97.18 ± 1.23 μM, respectively) against PTR1, compared with trimethoprim (positive control) (IC 50  = 21.07 ± 1.6 μM). Moreover, the results were further validated via molecular docking and molecular dynamics (MD) simulations. Compound 1 showed a strong affinity to the binding site with a docking score of -11.83, along with the formation of a stable protein-ligand complex over the trajectory of 100 ns. Besides, compounds 1-8 were found to be non-cytotoxic on BJ (human fibroblast) cells.