Benzimidazole derivatives endowed with potent antileishmanial activity

Two sets of benzimidazole derivatives were synthesised and tested in vitro for activity against promastigotes of Leishmania tropica and L. infantum. Most of the tested compounds resulted active against both Leishmania species, with IC 50 values in the low micromolar/sub-micromolar range. Among the s...

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Bibliographic Details
Published in:Journal of enzyme inhibition and medicinal chemistry 2018, Vol.33 (1), p.210-226
Main Authors: Tonelli, Michele, Gabriele, Elena, Piazza, Francesca, Basilico, Nicoletta, Parapini, Silvia, Tasso, Bruno, Loddo, Roberta, Sparatore, Fabio, Sparatore, Anna
Format: Article
Language:English
Subjects:
2-benzyl-1-lupinylbenzimidazole derivatives
alkyl benzimidazolium salts
Animals
anti-leishmania agents
Antiprotozoal Agents - chemical synthesis
Antiprotozoal Agents - chemistry
Antiprotozoal Agents - pharmacology
Benzimidazoles - chemical synthesis
Benzimidazoles - chemistry
Benzimidazoles - pharmacology
Cell Line
Cell Survival - drug effects
Chlorocebus aethiops
Dose-Response Relationship, Drug
Humans
Leishmania infantum - drug effects
Leishmania tropica - drug effects
Leishmania tropica and infantum
Molecular Structure
Parasitic Sensitivity Tests
promastigotes
Research Paper
Structure-Activity Relationship
Vero Cells
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Summary:Two sets of benzimidazole derivatives were synthesised and tested in vitro for activity against promastigotes of Leishmania tropica and L. infantum. Most of the tested compounds resulted active against both Leishmania species, with IC 50 values in the low micromolar/sub-micromolar range. Among the set of 2-(long chain)alkyl benzimidazoles, whose heterocyclic head was quaternised, compound 8 resulted about 100-/200-fold more potent than miltefosine, even if the selectivity index (SI) versus HMEC-1 cells was only moderately improved. In the set of 2-benzyl and 2-phenyl benzimidazoles, bearing a basic side chain in position 1, compound 28 (2-(4-chlorobenzyl)-1-lupinyl-5-trifluoromethylbenzimidazole) was 12-/7-fold more potent than miltefosine, but exhibited a further improved SI. Therefore, compounds 8 and 28 represent interesting hit compounds, susceptible of structural modification to improve their safety profiles.
ISSN:1475-6366
1475-6374
DOI:10.1080/14756366.2017.1410480