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

Seven 3-styrylcoumarins were tested for antileishmanial activity against (Viannia) amastigotes. Cytotoxic activity was also evaluated against mammalian U-937 cells. The 3-methoxy-4-hydroxy coumarin derivative was the most active with an IC 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 had docking preference by the -myristoyltransferase (-NMT) of , showing a higher docking score of - 10.1 kcal mol 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 /-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, 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 . Altogether, coumarin could be addressed as starting point for further pharmacological studies concerning the therapeutic leishmaniasis intervention.