Synthesis and docking studies of dihydrobenzofuran neolignan analogues as antileishmanial agents

Many thousands of new cases of Leishmaniasis, a worldwide distributed parasitic disease, are recorded every year. New effective and low-cost treatments are urgently needed. Natural products, as a well-known source of biologically active compounds, constitute a very important starting point. Specifically, dihydrobenzofuran neolignan analogues have demonstrated antileishmanial activity [1]. Therefore, and continuing our research on antileishmanial neolignans, a set of 15 dihydrobenzofurans were synthesized and tested in vitro against axenic amastigotes of Leishmania donovani. Cytotoxicity was also determined and selectivity indexes calculated.

The synthesized compounds included variations in the size of the lateral ester chains and the substitution on the aromatic moieties (Figure 1). In general, the former one affected stronger the antileishmanial activity than the latter. Even though no specific SAR's could be established so far, the experimentally measured activity was found to be linearly correlated with that previously predicted by 3D-QSAR modeling [2].

Fig. 1: Chemical structures and activity data of the three most active compounds. *All compounds were synthesized as racemic mixtures.

In search for potential molecular targets, a docking study was carried out using a set of ten different protein structures from L. donovani and one from L. major. Several of the docked compounds (n= 75), showed relatively favorable scores, suggesting potentially strong interactions with some of the proteins and possible inhibition. Most interestingly, the experimental activity of the available compounds was linearly correlated with the docking scores for N-myristoyl transferase, indicating a possible mode of action. Nevertheless, further SAR and mechanistic studies are still required.

[1] Van Miert S, Van Dyck S, Schmidt TJ, Brun R, Vlietinck A, Lemière G, Pieters L. Bioorg Med Chem 2005; 13: 661 – 669.

[2] Bernal FA, Schmidt TJ. Planta Med 2016; 82(S 01): S1-S381.