Exploring Lamiaceae diterpenoids as potential multitarget therapeutics for leishmaniasis and chagas disease.

Neglected tropical diseases such as Leishmaniasis and Chagas disease remain critical public health challenges. This study applied ligand-based virtual screening to a dataset of 4,150 secondary metabolites from the Lamiaceae family, aiming to identify multitarget molecules against four Leishmania species (L. infantum, L. donovani, L. amazonensis, and L. braziliensis) and Trypanosoma cruzi forms. Random forest models exhibited high accuracy (over 72%), leading to the identification of 82 molecules with potential multitarget activity across five of six predictive models. Nineteen prioritized molecules were subjected to molecular docking simulations targeting key enzymes-including sterol 14-alpha demethylase, glucose-6-phosphate dehydrogenase, dihydroorotate dehydrogenase, nucleoside diphosphate kinase, tryparedoxin peroxidase, and cruzain-with compounds 12, 18, and 19 exhibiting a high binding affinity across multiple targets. In vitro assays confirmed the predicted activity of selected molecules (3, 4, and 5) against Leishmania and T. cruzi. Importantly, these molecules represent novel findings, with antileishmanial or antitrypanosomal activities that have not been previously reported. The results highlight their potential as multitarget therapeutic candidates for neglected tropical diseases, paving the way for further biological evaluation and development.