Discovery of benzimidazole-based Leishmania mexicana cysteine protease CPB 2.8 Δ CTE inhibitors as potential therapeutics for leishmaniasis

Publication type:
Journal article
Metadata:
Autoren
  • Laura De Luca
  • Stefania Ferro
  • Maria Rosa Buemi
  • Anna-Maria Monforte
  • Rosaria Gitto
  • Tanja Schirmeister
  • Louis Maes
  • Antonio Rescifina
  • Nicola Micale
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000443302700001&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1111/cbdd.13326
eISSN
1747-0285
Externe Identifier
  • Clarivate Analytics Document Solution ID: GS1PP
  • PubMed Identifier: 29729080
ISSN
1747-0277
Ausgabe der Veröffentlichung
3
Zeitschrift
CHEMICAL BIOLOGY & DRUG DESIGN
Schlüsselwörter
  • antileishmanial agents
  • benzimidazole derivatives
  • docking studies
  • in silico profiling
  • Leishmania mexicana CPB2.8
Paginierung
1585 - 1596
Datum der Veröffentlichung
2018
Status
Published
Titel
Discovery of benzimidazole-based <i>Leishmania mexicana</i> cysteine protease CPB2.8CTE inhibitors as potential therapeutics for leishmaniasis
Sub types
  • Article
Ausgabe der Zeitschrift
92

Data source: Web of Science (Lite)

Other metadata sources:
Abstract
<jats:p>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‐1<jats:italic>H</jats:italic>‐benzo[<jats:italic>d</jats:italic>]imidazole derivatives (<jats:bold>9a–d</jats:bold>) showing affinity in the submicromolar range (<jats:italic>K</jats:italic><jats:sub>i</jats:sub> = 0.15–0.69 μM) toward <jats:italic>Leishmania mexicana</jats:italic><jats:styled-content style="fixed-case">CPB</jats:styled-content>2.8Δ<jats:styled-content style="fixed-case">CTE</jats:styled-content>, one of the more promising targets for antileishmanial drug design. The compounds confirmed activity in vitro against intracellular amastigotes of <jats:italic>Leishmania infantum</jats:italic> with the best result being obtained with derivative <jats:bold>9d</jats:bold> (<jats:styled-content style="fixed-case">IC</jats:styled-content><jats:sub>50</jats:sub> = 6.8 μM), although with some degree of cytotoxicity (<jats:styled-content style="fixed-case">CC</jats:styled-content><jats:sub>50</jats:sub> = 8.0 μM on <jats:styled-content style="fixed-case">PMM</jats:styled-content> and <jats:styled-content style="fixed-case">CC</jats:styled-content><jats:sub>50</jats:sub> = 32.0 μM on <jats:styled-content style="fixed-case">MCR</jats:styled-content>‐5). In silico molecular docking studies and <jats:styled-content style="fixed-case">ADME</jats:styled-content>‐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.</jats:p>
Autoren
  • Laura De Luca
  • Stefania Ferro
  • Maria Rosa Buemi
  • Anna‐Maria Monforte
  • Rosaria Gitto
  • Tanja Schirmeister
  • Louis Maes
  • Antonio Rescifina
  • Nicola Micale
DOI
10.1111/cbdd.13326
eISSN
1747-0285
ISSN
1747-0277
Ausgabe der Veröffentlichung
3
Zeitschrift
Chemical Biology &amp; Drug Design
Sprache
en
Online publication date
2018
Paginierung
1585 - 1596
Datum der Veröffentlichung
2018
Status
Published
Herausgeber
Wiley
Herausgeber URL
http://dx.doi.org/10.1111/cbdd.13326
Datum der Datenerfassung
2023
Titel
Discovery of benzimidazole‐based <i>Leishmania mexicana</i> cysteine protease <scp>CPB</scp>2.8Δ<scp>CTE</scp> inhibitors as potential therapeutics for leishmaniasis
Ausgabe der Zeitschrift
92

Data source: Crossref

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<sub>i</sub>  = 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<sub>50</sub>  = 6.8 μM), although with some degree of cytotoxicity (CC<sub>50</sub>  = 8.0 μM on PMM and CC<sub>50</sub>  = 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.
Addresses
  • Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy.
Autoren
  • Laura De Luca
  • Stefania Ferro
  • Maria Rosa Buemi
  • Anna-Maria Monforte
  • Rosaria Gitto
  • Tanja Schirmeister
  • Louis Maes
  • Antonio Rescifina
  • Nicola Micale
DOI
10.1111/cbdd.13326
eISSN
1747-0285
Externe Identifier
  • PubMed Identifier: 29729080
Open access
false
ISSN
1747-0277
Ausgabe der Veröffentlichung
3
Zeitschrift
Chemical biology & drug design
Schlüsselwörter
  • Cell Line
  • Humans
  • Leishmania mexicana
  • Leishmaniasis
  • Benzimidazoles
  • Protozoan Proteins
  • Cysteine Proteinase Inhibitors
  • Antiprotozoal Agents
  • Drug Evaluation, Preclinical
  • Inhibitory Concentration 50
  • Cell Survival
  • Binding Sites
  • Protein Structure, Tertiary
  • Hydrogen Bonding
  • Cysteine Proteases
  • Enzyme Assays
  • Molecular Docking Simulation
Sprache
eng
Medium
Print-Electronic
Online publication date
2018
Paginierung
1585 - 1596
Datum der Veröffentlichung
2018
Status
Published
Datum der Datenerfassung
2018
Titel
Discovery of benzimidazole-based Leishmania mexicana cysteine protease CPB2.8ΔCTE inhibitors as potential therapeutics for leishmaniasis.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
92

Data source: Europe PubMed Central

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 (Ki  = 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 (IC50  = 6.8 μM), although with some degree of cytotoxicity (CC50  = 8.0 μM on PMM and CC50  = 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.
Date of acceptance
2018
Autoren
  • Laura De Luca
  • Stefania Ferro
  • Maria Rosa Buemi
  • Anna-Maria Monforte
  • Rosaria Gitto
  • Tanja Schirmeister
  • Louis Maes
  • Antonio Rescifina
  • Nicola Micale
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/29729080
DOI
10.1111/cbdd.13326
eISSN
1747-0285
Ausgabe der Veröffentlichung
3
Zeitschrift
Chem Biol Drug Des
Schlüsselwörter
  • Leishmania mexicanaCPB2.8
  • antileishmanial agents
  • benzimidazole derivatives
  • docking studies
  • in silico profiling
  • Antiprotozoal Agents
  • Benzimidazoles
  • Binding Sites
  • Cell Line
  • Cell Survival
  • Cysteine Proteases
  • Cysteine Proteinase Inhibitors
  • Drug Evaluation, Preclinical
  • Enzyme Assays
  • Humans
  • Hydrogen Bonding
  • Inhibitory Concentration 50
  • Leishmania mexicana
  • Leishmaniasis
  • Molecular Docking Simulation
  • Protein Structure, Tertiary
  • Protozoan Proteins
Sprache
eng
Country
England
Paginierung
1585 - 1596
Datum der Veröffentlichung
2018
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2019
Titel
Discovery of benzimidazole-based Leishmania mexicana cysteine protease CPB2.8ΔCTE inhibitors as potential therapeutics for leishmaniasis.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
92

Data source: PubMed

Autoren
  • Laura De Luca
  • Stefania Ferro
  • Maria Rosa Buemi
  • Anna-Maria Monforte
  • Rosaria Gitto
  • Tanja Schirmeister
  • Louis Maes
  • Antonio Rescifina
  • Nicola Micale
Zeitschrift
Chemical Biology & Drug Design
Datum der Veröffentlichung
2018
Datum der Datenerfassung
2021
Titel
Discovery of benzimidazole-based Leishmania mexicana cysteine protease CPB 2.8 Δ CTE inhibitors as potential therapeutics for leishmaniasis
Sub types
  • article

Data source: Manual

Beziehungen:
Property of

Tools