There is an urgent need for the discovery of new antileishmanial drugs with a new mechanism of action. Type 2 NADH dehydrogenase from Leishmania infantum (LiNDH2) is an enzyme of the parasite’s respiratory system, which catalyzes the electron transfer from NADH to ubiquinone without coupled proton pumping. In previous studies of the related NADH: ubiquinone oxidoreductase crystal structure from Saccharomyces cerevisiae, two ubiquinone-binding sites (UQ_I and UQ_II) were identified and shown to play an important role in the NDH-2-catalyzed oxidoreduction reaction. Based on the available structural data, we developed a three-dimensional structural model of LiNDH2 using homology detection methods and performed an in silico virtual screening campaign to search for potential inhibitors targeting the LiNDH2 ubiquinone-binding site 1—UQ_I. Selected compounds displaying favorable properties in the computational screening experiments were assayed for inhibitory activity in the structurally similar recombinant NDH-2 from S. aureus and leishmanicidal activity was determined in the wild-type axenic amastigotes and promastigotes of L. infantum. The identified compound, a substituted 6-methoxy-quinalidine, showed promising nanomolar leishmanicidal activity on wild-type axenic promastigotes and amastigotes of L. infantum and the potential for further development.

Arginase, a drug target for the treatment of leishmaniasis, is involved in the biosynthesis of polyamines. Flavonoids are interesting natural compounds found in many foods and some of them may inhibit this enzyme. The MetIDB database containing 5667 compounds was screened using an EIIP/AQVN filter and 3D QSAR to find the most promising candidate compounds. In addition, these top hits were screened in silico versus human arginase and an anti-target battery consisting of cytochromes P450 2a6, 2c9, 3a4, sulfotransferase, and the pregnane-X-receptor in order to flag their possible interactions with these proteins involved in the metabolism of substances. The resulting compounds may have promise to be further developed for the treatment of leishmaniasis.

Due to the lack of approved vaccines against human leishmaniasis and the limitations of the current chemotherapy inducing side effects and drug resistance, development of new, effective chemotherapeutic agents is essential. This study describes the synthesis of a series of novel oxadiazoles and indolizine-containing compounds. The compounds were screened in silico using an EIIP/AQVN filter followed by ligand-based virtual screening and molecular docking to parasite arginase. Top hits were further screened versus human arginase and finally against an anti-target battery to tag their possible interactions with proteins essential for the metabolism and clearance of many substances. Eight candidate compounds were selected for further experimental testing. The results show measurable in vitro anti-leishmanial activity for three compounds. One compound with an IC₅₀ value of 2.18 µM on Leishmania donovani intramacrophage amastigotes is clearly better positioned than the others as an interesting molecular template for further development of new anti-leishmanial agents.

Background/Objectives: Drug repurposing is one of the possible sources of new anthelmintics. Afoxolaner is a insecticide/acaricide that acts on the insect GABA receptor and regulates uptake of chloride ions. We examined the interaction of afoxolaner with GABA receptors of nematodes. Methods: We tested the effects of afoxolaner on the motility of the free-living nematode C. elegans and its effect on the contractions/relaxation of the parasitic nematode A. suum. By means of structural bioinformatics, we analyzed the potential binding sites of afoxolaner on the nematode synaptic/exrasynaptic GABA receptor. Results: Afoxolaner inhibited the development of adult C. elegans, significantly reduced the distance traveled, movement speed, and motility score. Afoxolaner significantly inhibited the contractions of the A. suum neuromuscular preparation by increasing the EC₅₀ value of ACh but not changed the E_max. However, afoxolaner neutralized the inhibitory effect of GABA, significantly reduced the EC₅₀ of ACh and increased E_max. In the relaxation study, afoxolaner potentiates GABA-evoked relaxation but inhibited piperazine-induced relaxation. Conclusions: Pharmacological effect of afoxolaner on GABA receptors in nematodes can be defined in two ways: when contractions were induced by ACh, afoxolaner behaves as a partial agonist/antagonist, which would involve binding to an orthosteric site on the receptor. Probably this effect is realized on synaptic GABA receptors between inhibitory interneurons and motoneurons. However, when relaxation is induced by activation of an extrasynaptic GABA receptor, afoxolaner exhibits the characteristics of positive allosteric modulator, it does not cause relaxation by itself, but enhances the effect of GABA and antagonizes the action of piperazine.