Abstract
Arginase catalyzes the hydrolysis of l-arginine into l-ornithine and urea, acting as a key enzyme in the biosynthesis of polyamines. Leishmania growth and survival is dependent on polyamine biosynthesis; therefore, inhibition of Leishmania arginase may be a promising therapeutic strategy. Here, we evaluated a series of thirty-six chalcone derivatives as potential inhibitors of Leishmania infantum arginase (LiARG). In addition, the activity of selected inhibitors against L. infantum parasites was assessed in vitro. Seven compounds exhibited LiARG inhibition above 50% at 100 μM. Among them, compounds LC41, LC39, and LC32 displayed the greatest inhibition values (72.3 ± 0.3%, 71.9 ± 11.6%, and 69.5 ± 7.9%, respectively). Molecular docking studies predicted hydrogen bonds and hydrophobic interactions between the most active chalcones (LC32, LC39, and LC41) and specific residues from LiARG's active site, such as His140, Asn153, His155, and Ala193. Compound LC32 showed the highest activity against L. infantum promastigotes (IC50 of 74.1 ± 10.0 μM), whereas compounds LC39 and LC41 displayed the best results against intracellular amastigotes (IC50 of 55.2 ± 3.8 and 70.4 ± 9.6 μM, respectively). Moreover, compound LC39 showed more selectivity against parasites than host cells (macrophages), with a selectivity index (SI) of 107.1, even greater than that of the reference drug Fungizone®. Computational pharmacokinetic and toxicological evaluations showed high oral bioavailability and low toxicity for the most active compounds. The results presented here support the use of substituted chalcone skeletons as promising LiARG inhibitors and antileishmanial drug candidates.
Highlights
Leishmania infantum is the etiological agent of visceral leishmaniasis (VL), a lethal infectious disease that afflicts neglected populations mainly distributed in Africa, Asia and Latin America
To further investigate the nature of the antileishmanial activity, we evaluated whether treatment with the selected chalcone derivatives (LC32, LC34, LC39, and LC41) increased NO production by L. infantum-infected macrophages
Our results suggest that the chalcone derivatives were unable to modulate the host immune response and their antileishmanial activity may occur in a nitrosative stress-independent fashion, most likely directly on the parasite by inhibiting Leishmania arginase
Summary
Leishmania infantum is the etiological agent of visceral leishmaniasis (VL), a lethal infectious disease that afflicts neglected populations mainly distributed in Africa, Asia and Latin America. Arginase plays a pivotal role for the survival of Leishmania. This enzyme acts as a binuclear manganese metalloprotease responsible for L-arginine bioconversion into ornithine, which represents the first step of the polyamine pathway. In the past few years, Leishmania arginase (ARG) has been proposed as a potential target for new drug candidates of natural (GirardThernier et al, 2015; Glisic et al, 2016; da Silva et al, 2019) or synthetic origin (Crizanto de Lima et al, 2019). The thiol pathway is essential for the elimination of reactive oxygen species (ROS) generated by the macrophage oxidative burst and establishment of infection (Ilari et al, 2017; Pessenda and da Silva, 2020). Muleme et al (2009) demonstrated that Leishmania major ARG null mutants showed phenotypes of diminished proliferation in vitro (macrophage infection) and in vivo (Balb/C mouse infection) contexts; this finding reinforces that ARG is essential for Leishmania pathophysiology and is an intriguing target for new therapeutics
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