Investigation of the anti-leishmanial potential of triazole-linked carvacrol–coumarin derivatives: a docking, molecular dynamics, MM/GBSA toxicity approach

Abstract

Leishmaniasis is a neglected disease in tropical and subtropical regions caused by obligate intracellular parasitic protozoa of the genus Leishmania ssp, which can infect humans and animals. In the search for new drugs to treat leishmaniasis, natural compounds have emerged as therapeutic alternatives, such as carvacrol and coumarins, which are considered valuable therapeutic agents and intermediates for organic syntheses associated with other pharmacophores such as triazoles, coumarins, alkyl groups to in improve in pharmacological in properties. This study aims to evaluate the potential of hybrid compounds of coumarins and carvacrol associated with triazole pharmacophores by analyzing the influence of the aliphatic carbon chain and their interactions with the enzyme N-myristoyltransferase (NMT) of Leishmania spp. using in silico methods. It was observed that the Tc1 ligand showed superior affinity with the NMT protein, establishing interactions with residues in the same region as the crystallized inhibitor, and showed better affinity compared to the coumarin and carvacrol. Molecular dynamics simulations analyze the stability and free binding energy (∆G_bind) of the Tc1-NMT complex over 200 ns. The RMSD indicated system remained stable, with ∆G_bind of  − 33.80 kcal/mol. These results provide insights into a possible mechanism of inhibition of the natural product-derived Tc1 ligand toward the NMT transferase enzyme, which plays a vital role in the protozoan life cycle. The hybrids exhibited a low toxicity profile in rats, primarily via the oral route, commonly used in pre-clinical trials.

Graphical abstract

Triazole conjugated carvacrol–coumarin derivatives with anti-leishmanial potential