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Structure-Activity Study on Substituted, Core-Extended, and Dyad Naphthalene Diimide G-Quadruplex Ligands Leading to Potent Antitrypanosomal Agents.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2024 Jul 11; Vol. 67 (13), pp. 10643-10654. Date of Electronic Publication: 2024 Jun 26. - Publication Year :
- 2024
-
Abstract
- Several G-quadruplex nucleic acid (G4s) ligands have been developed seeking target selectivity in the past decade. Naphthalene diimide (NDI)-based compounds are particularly promising due to their biological activity and red-fluorescence emission. Previously, we demonstrated the existence of G4s in the promoter region of parasite genomes, assessing the effectiveness of NDI-derivatives against them. Here, we explored the biological activity of a small library of G4-DNA ligands, exploiting the NDI pharmacophore, against both Trypanosoma brucei and Leishmania major parasites. Biophysical and biological assays were conducted. Among the various families analyzed, core-extended NDIs exhibited the most promising results concerning the selectivity and antiparasitic effects. NDI 16 emerged as the most potent, with an IC <subscript>50</subscript> of 0.011 nM against T. brucei and remarkable selectivity vs MRC-5 cells (3454-fold). Fascinating, 16 is 480-fold more potent than the standard drug pentamidine (IC <subscript>50</subscript> = 5.3 nM). Cellular uptake and parasite localization were verified by exploiting core-extended NDI red-fluorescent emission.
- Subjects :
- Structure-Activity Relationship
Ligands
Humans
Cell Line
G-Quadruplexes drug effects
Naphthalenes pharmacology
Naphthalenes chemistry
Imides chemistry
Imides pharmacology
Trypanosoma brucei brucei drug effects
Trypanocidal Agents pharmacology
Trypanocidal Agents chemistry
Trypanocidal Agents chemical synthesis
Leishmania major drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 67
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 38924701
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.4c00135