| Summary: | Leishmaniasis is endemic in at least 98 countries. Due to the high toxicity and resistance associated with the drugs, we chose lignans as an alternative, due to their favorable properties of absorption, distribution, metabolism, excretion, and toxicity (ADMET). To investigate their leishmanicidal potential, the biological activities of a set of 160 lignans were predicted using predictive models that were built using data for <i>Leishmania</i> <i>major</i> and <i>L. (Viannia) braziliensis</i>. A combined analysis, based on ligand and structure, and several other computational approaches were used. The results showed that the combined analysis was able to select 11 lignans with potential activity against <i>L. major</i> and 21 lignans against <i>L. braziliensis</i>, with multitargeting effects and low or no toxicity. Of these compounds, four were isolated from the species <i>Justicia</i> <i>aequilabris</i> (Nees) Lindau. All of the identified compounds were able to inhibit the growth of <i>L. braziliensis</i> promastigotes, with the most active compound, (<b>159</b>) epipinoresinol-4-<i>O</i>-β-<span style="font-variant: small-caps;">d</span>-glucopyranoside, presenting an IC<sub>50</sub> value of 5.39 µM and IC<sub>50</sub> value of 36.51 µM for <i>L. major</i>. Our findings indicated the potential of computer-aided drug design and development and demonstrated that lignans represent promising prototype compounds for the development of multitarget drugs against leishmaniasis.
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