3-styrylcoumarin scaffold-based derivatives as a new approach for leishmaniasis intervention: biological and molecular modeling studies

This is the authors' abstract. We don't add key points for this paper.

Seven 3-styrylcoumarins were tested for antileishmanial activity against Leishmania (Viannia) panamensis amastigotes. Cytotoxic activity was also evaluated against mammalian U-937 cells. The 3-methoxy-4-hydroxy coumarin derivative 6 was the most active with an IC 50 of 40.5 µM, and did not reveal any conspicuous toxicity toward mammalian U-937 cells. Therefore, it may have potential to be considered as candidate for antileishmanial drug development. Further, among several druggable Leishmania targets, molecular docking studies revealed that compound 6 had docking preference by the N -myristoyltransferase ( Lp -NMT) of Leishmania panamensis , showing a higher docking score of − 10.1 kcal mol −1 than positive controls and making this protein as a presumably druggable target for this compound. On the other hand, molecular dynamics simulations affirm the docking hypothesis, showing a conformational stability of the 6 / Lp -NMT complex throughout 100 ns simulation. Moreover, the molecular mechanics/Poisson–Boltzmann surface area method also support the docking findings, revealing a total free energy of binding of − 47.26 ± 0.08 kcal mol −1 , and identifying through energy decomposition analysis that those key aminoacids are contributing strongly to ligand binding. Finally, an optimal pharmacokinetic profile was also estimated for 6 . Altogether, coumarin 6 could be addressed as starting point for further pharmacological studies concerning the therapeutic leishmaniasis intervention.