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

Irene Betancourt-Conde,Erick Sierra-Campos,Rafael Castillo,Lilián Yépez-Mulia,Claudia Avitia-Domínguez,Juan A Hermoso,Alfredo Téllez-Valencia,Antonio Romo-Mancillas,Alicia Hernández-Campos,Sara T Méndez,Mónica Valdez-Solana,Jesús Oria-Hernández,Siseth Martínez-Caballero

doi:10.3390/ijms222413613

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.

Highlights

Leishmaniasis is a neglected tropical disease transmitted by sandfly vector (Phlebotomus or Lutzomyia) via anthroponotic or zoonotic cycles [1]
With the aim to find new LmARG inhibitors that recognize the active site of the enzyme, we performed a virtual screening, using molecular docking, of our in-house library of 450 benzimidazole derivatives using the crystal structure of LmARG (PDB ID: 4IU0)
The changing of a methylcarbamate in position 2 of the benzimidazole nucleus by an acetyl group, reduce almost 50% the inhibitory potency

Summary

Introduction

Leishmaniasis is a neglected tropical disease transmitted by sandfly vector (Phlebotomus or Lutzomyia) via anthroponotic or zoonotic cycles [1]. The three main forms of leishmaniasis include cutaneous (CL), mucosal (MCL) and visceral leishmaniasis (VL) [2]. This disease affects 98 countries, and it is estimated that approximately 2 million of new cases occur each year and more than 350 million people are at risk [3]. The first line treatment against the leishmaniasis consist in sodium stibogluconate (Pentostam) and meglumine antimoniate (Glucantime) [4]. Their use is limited due to their toxicity and the apparition of resistance strains [5]. Pentamidine and Amphotericin B are used as second line drugs, but as well as antimonials, their use is limited due to its toxicity and the parasite resistance [6,7]. Miltefosine is the only existing oral drug to the treatment of leishmaniasis, its use has not been satisfactory due to the potential parasite resistance, it is necessary to continue with its pharmacovigilance [8]

Methods

Results

Discussion

Conclusion