Discovery of benzimidazole‐based Leishmania mexicana cysteine protease CPB2.8ΔCTE inhibitors as potential therapeutics for leishmaniasis

Abstract

Chemotherapy is currently the only effective approach to treat all forms of leishmaniasis. However, its effectiveness is severely limited due to high toxicity, long treatment length, drug resistance, or inadequate mode of administration. As a consequence, there is a need to identify new molecular scaffolds and targets as potential therapeutics for the treatment of this disease. We report a small series of 1,2-substituted-1H-benzo[d]imidazole derivatives (9a-d) showing affinity in the submicromolar range (K = 0.15-0.69 μM) toward Leishmania mexicanaCPB2.8ΔCTE, one of the more promising targets for antileishmanial drug design. The compounds confirmed activity in vitro against intracellular amastigotes of Leishmania infantum with the best result being obtained with derivative 9d (IC = 6.8 μM), although with some degree of cytotoxicity (CC = 8.0 μM on PMM and CC = 32.0 μM on MCR-5). In silico molecular docking studies and ADME-Tox properties prediction were performed to validate the hypothesis of the interaction with the intended target and to assess the drug-likeness of these derivatives.

Systematic in silico Evaluation of Leishmania spp. Proteomes for Drug Discovery

“…Alcohol dehydrogenase proteins have been associated with miltefosine resistance in Leishmania parasites, as they are also involved with the reduction of reactive oxygen species and protection against oxidative stress (Carnielli et al, 2014;Hefnawy et al, 2017). This class of proteins has also been described as a potential pharmacological target in analyzes performed using the T. cruzi proteome (Alves- Ferreira et al, 2009) and in our analyzes, these proteins (LbrM.30.2040, LinJ.30.2100) were inferred as potential targets for formamide compounds, which are known to inhibit their activity (Gibbons and Hurley, 2004;Plapp, 2010;Espuelas et al, 2012), and targets for benzimidazolebased compounds, drugs for which leishmanicidal activity has been reported and used as antiparasitic agents that act in inhibiting tubulin polymerization (Mota et al, 2014;De Luca et al, 2018;Sánchez-Salgado et al, 2018).…”

Of Drugs and Trypanosomatids: New Tools and Knowledge to Reduce Bottlenecks in Drug Discovery

“…Distinct endopeptidases like cathepsin-L-like CPB2.8 have emerged as exploitable drug targets in leishmaniasis. De Luca et al (2018) identified a group of substituted benzimidazole derivatives that displayed strong (nanomolar) affinity for the protease from L. mexicana [ 96 ]. One of the compounds demonstrated a good bioavailability profile with ADMET analysis, implying it is a good future drug candidate.…”

Multiscale Process Modelling in Translational Systems Biology of Leishmania major: A Holistic view

“…pounds, consisting of fusion of benzene and imidazole, and are known to have potent inhibitory activity [43][44][45][46] , including anti-viral, anti-bacterial, anti-leishmanial [47][48][49][50] . Similarly, thiosemicarbazones have also been broadly studied due to their role as antibacterial, antiprotozoal, and antiviral activity [51][52][53][54][55] .…”