6533b7cffe1ef96bd125864e
RESEARCH PRODUCT
Discovery of benzimidazole-based Leishmania mexicana cysteine protease CPB2.8ΔCTE inhibitors as potential therapeutics for leishmaniasis
Stefania FerroLouis MaesLaura De LucaMaria Rosa BuemiAnna-maria MonforteAntonio RescifinaTanja SchirmeisterRosaria GittoNicola Micalesubject
BenzimidazoleCell SurvivalIn silicoLeishmania mexicanaAntiprotozoal AgentsDrug Evaluation PreclinicalProtozoan ProteinsDrug resistanceCysteine Proteinase InhibitorsPharmacologyAntileishmanial agents Benzimidazole derivatives Docking studies In silico profiling Leishmania mexicanaCPB2.8 Biochemistry Molecular Medicine01 natural sciencesBiochemistryLeishmania mexicanaCell LineInhibitory Concentration 50chemistry.chemical_compoundCysteine ProteasesDrug DiscoverymedicineHumansAmastigoteLeishmaniasisBiologyEnzyme AssaysPharmacologyBinding Sitesbiology010405 organic chemistryChemistryPharmacology. TherapyOrganic ChemistryHydrogen BondingLeishmaniasisbiology.organism_classificationmedicine.diseaseLeishmaniaProtein Structure Tertiary0104 chemical sciencesMolecular Docking Simulation010404 medicinal & biomolecular chemistryChemistryMolecular MedicineBenzimidazolesHuman medicineLeishmania infantumdescription
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 (9ad) showing affinity in the submicromolar range (Ki = 0.150.69 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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2018-01-01 | Chemical biology and drug design |