Benzimidazole Derivatives as New and Selective Inhibitors of Arginase from Leishmania mexicana with Biological Activity against Promastigotes and Amastigotes

Abstract

Leishmaniasis is a disease caused by parasites of the Leishmania genus that affects 98 countries worldwide, 2 million of new cases occur each year and more than 350 million people are at risk. The use of the actual treatments is limited due to toxicity concerns and the apparition of resistance strains. Therefore, there is an urgent necessity to find new drugs for the treatment of this disease. In this context, enzymes from the polyamine biosynthesis pathway, such as arginase, have been considered a good target. In the present work, a chemical library of benzimidazole derivatives was studied performing computational, enzyme kinetics, biological activity, and cytotoxic effect characterization, as well as in silico ADME-Tox predictions, to find new inhibitors for arginase from Leishmania mexicana (LmARG). The results show that the two most potent inhibitors (compounds 1 and 2) have an I50 values of 52 μM and 82 μM, respectively. Moreover, assays with human arginase 1 (HsARG) show that both compounds are selective for LmARG. According to molecular dynamics simulation studies these inhibitors interact with important residues for enzyme catalysis. Biological activity assays demonstrate that both compounds have activity against promastigote and amastigote, and low cytotoxic effect in murine macrophages. Finally, in silico prediction of their ADME-Tox properties suggest that these inhibitors support the characteristics to be considered drug candidates. Altogether, the results reported in our study suggest that the benzimidazole derivatives are an excellent starting point for design new drugs against leishmanisis.

Synthesis of Antiprotozoal 2-(4-Alkyloxyphenyl)-Imidazolines and Imidazoles and Their Evaluation on Leishmania mexicana and Trypanosoma cruzi

“…Imidazolines containing short chains (22)(23)(24)(25)(26) were not included because these compounds provide good yields with both conventional heating and MW. The results of reacting compounds with carbon chains C 5 -C 9 are shown in Table 3 (27)(28)(29)(30)(31), showing almost the same yields with MW and ultrasound energy, but in half the time with the latter.…”

Metalloenzyme Inhibitors against Zoonotic Infections: Focus on Leishmania and Schistosoma

“…90 Crystal structures of L. mexicana and S. mansoni arginase have been solved, furnishing useful insights for the development of new chemical entities able to interfere with the infections sustained by these parasites. 91,92 Arginase from L. mexicana (LmARG) is a metalloenzyme, belonging to the α/β family, characterized by the presence of eight-stranded β-sheets, edged on both sides by α-helices and stabilized by intermolecular ionic interactions and hydrogen bonds. Two manganese ions in the active site are essential for the catalytic activity, together with three catalytic residues, Glu288 which participates in substrate recognition, Asp141 which stabilizes the hydroxide ion, and His139 that is a proton shuttle.…”

“…Furthermore, the loop formed by residues Leu161–Cys172 and the helix formed by Ile219–Val230 in hARG ( Lm ARG numeration) shows a different conformation in Lm ARG. Finally, some differences can be observed in the intermolecular interactions that stabilize the homotrimer …”

“…Finally, some differences can be observed in the intermolecular interactions that stabilize the homotrimer. 91 S. mansoni arginase (SmARG) monomer presents a similar folding to the unliganded human arginase I (PDB: 2ZAV), with a modest amino acid sequence identity (42%), but with an almost identical binuclear manganese cluster. Moreover, even in the case of SmARG, the monomers oligomerize to form a homotrimer, with a total buried surface area of 10980 Å 2 (31% of the total solvent-accessible surface area).…”

“…Crystal structures of L. mexicana and S. mansoni arginase have been solved, furnishing useful insights for the development of new chemical entities able to interfere with the infections sustained by these parasites. , …”