Systematic search for benzimidazole compounds and derivatives with antileishmanial effects

Abstract

Leishmaniasis is a neglected tropical disease that currently affects 12 million people, and over 1 billion people are at risk of infection. Current chemotherapeutic approaches used to treat this disease are unsatisfactory, and the limitations of these drugs highlight the necessity to develop treatments with improved efficacy and safety. To inform the rational design and development of more efficient therapies, the present study reports a chemoinformatic approach using the ChEMBL database to retrieve benzimidazole as a target scaffold. Our analysis revealed that a limited number of studies had investigated the antileishmanial effects of benzimidazoles. Among this limited number, L. major was the species most commonly used to evaluate the antileishmanial effects of these compounds, whereas L. amazonensis and L. braziliensis were used least often in the reported studies. The antileishmanial activities of benzimidazole derivatives were notably variable, a fact that may depend on the substitution pattern of the scaffold. In addition, we investigated the effects of a benzimidazole derivative on promastigotes and amastigotes of L. infantum and L. amazonensis using a novel fluorometric method. Significant antileishmanial effects were observed on both species, with L. amazonensis being the most sensitive. To the best of our knowledge, this chemoinformatic analysis represents the first attempt to determine the relevance of benzimidazole scaffolds for antileishmanial drug discovery using the ChEMBL database. The present findings will provide relevant information for future structure-activity relationship studies and for the investigation of benzimidazole-derived drugs as potential treatments for leishmaniasis.

State-of-the-art Review on the Antiparasitic Activity of Benzimidazolebased Derivatives: Facing Malaria, Leishmaniasis, and Trypanosomiasis

“…Sánchez-Salgado et al . [ 91 ] reported an interesting chemoinformatic approach using the ChEMBL database along with an additional literature search to recover the benzimidazole nucleus as a target scaffold. About 235 benzimidazoles were identified with activity against several L. species.…”

Drug Discovery for Cutaneous Leishmaniasis: A Review of Developments in the Past 15 Years

“…Thiazolopyrimidine derivatives were designed by Istanbullu et al (2020) to target L. major pteridine reductase 1 (LmPTR1); these researchers were able to identify one potent compound with potent activity against the purified enzyme, as well as IC 50 values of 7.5 µM and 2.69 µM against promastigote and intracellular amastigotes, respectively [116]. In addition to those mentioned above, other compound classes with activity against multiple CL-causing species were identified, including chalcone-like hybrids [117], monovalent ionophores [118], benzimidazole derivatives [119], and cruzioseptins [120].…”

Table_4.XLSX

“…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).…”