Natural products as inhibitors of recombinant cathepsin L of Leishmania mexicana

•Natural products were screened against L. mexicana cathepsin L (rCPB2.8).•A triterpene and some flavonoids are inhibitors of rCPB2.8.•The inhibitors of rCPB2.8 are partially noncompetitive and uncompetitive.•The mechanism would be an advantage in the search for selective inhibitors. Cysteine proteinases (cathepsins) from Leishmania spp. are promising molecular targets against leishmaniasis. Leishmania mexicana cathepsin L is essential in the parasite life cycle and a pivotal in virulence factor in mammals. Natural products that have been shown to display antileishmanial activity were screened as part of our ongoing efforts to design inhibitors against the L. mexicana cathepsin L-like rCPB2.8. Among them, agathisflavone (1), tetrahydrorobustaflavone (2), 3-oxo-urs-12-en-28-oic acid (3), and quercetin (4) showed significant inhibitory activity on rCPB2.8 with IC50 values ranging from 0.43 to 18.03 µM. The mechanisms of inhibition for compounds 1–3, which showed Ki values in the low micromolar range (Ki = 0.14–1.26 µM), were determined. The biflavone 1 and the triterpene 3 are partially noncompetitive inhibitors, whereas biflavanone 2 is an uncompetitive inhibitor. The mechanism of action established for these leishmanicidal natural products provides a new outlook in the search for drugs against Leishmania.