A new nonpolar N-hydroxy imidazoline lead compound with improved activity in a murine model of late-stage Trypanosoma brucei brucei infection is not cross-resistant with diamidines
| Autor: | Laura Lagartera, Harry P. de Koning, Anthonius A. Eze, Kayathiri Ganeshamoorthy, Florence Miller, Carlos H. Ríos Martínez, Christophe Dardonville, Marcel Kaiser, Fabienne Glacial, Tomás Herraiz |
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| Přispěvatelé: | Instituto de Quimica Médica (CSIC), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut de Radioprotection et de Sûreté Nucléaire (IRSN), University of Basel (Unibas), University of Glasgow, ICTAN Instituto de Ciencia y Tecnología de Alimentos y Nutrición, Consejo Superior de Investigaciones Científicas, CSIC 200470E658Consejo Superior de Investigaciones Científicas, CSIC 2008GB0021Consejo Superior de Investigaciones Científicas, CSIC PA1003015 |
| Rok vydání: | 2015 |
| Předmět: |
Trypanosoma brucei rhodesiense
[SDV]Life Sciences [q-bio] Trypanosoma brucei brucei Imidazoline receptor Trypanosoma brucei 03 medical and health sciences chemistry.chemical_compound Mice In vivo Animals Pharmacology (medical) Experimental Therapeutics Benzamide Imidazolines 030304 developmental biology Trypanocidal agent Pharmacology 0303 health sciences biology 030306 microbiology biology.organism_classification Trypanocidal Agents In vitro 3. Good health Disease Models Animal Infectious Diseases Trypanosomiasis African chemistry Biochemistry Microsome Female |
| Zdroj: | Antimicrobial Agents and Chemotherapy Antimicrobial Agents and Chemotherapy, 2015, 59 (2), pp.890-904. ⟨10.1128/AAC.03958-14⟩ Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 1098-6596 0066-4804 |
| Popis: | Copyright © 2015 American Society for Microbiology. All Rights Reserved. Treatment of late-stage sleeping sickness requires drugs that can cross the blood-brain barrier (BBB) to reach the parasites located in the brain. We report here the synthesis and evaluation of four new N-hydroxy and 12 new N-alkoxy derivatives of bisimidazoline leads as potential agents for the treatment of late-stage sleeping sickness. These compounds, which have reduced basicity compared to the parent leads (i.e., are less ionized at physiological pH), were evaluated in vitro against Trypanosoma brucei rhodesiense and in vivo in murine models of first- and second-stage sleeping sickness. Resistance profile, physicochemical parameters, in vitro BBB permeability, and microsomal stability also were determined. The N-hydroxy imidazoline analogues were the most effective in vivo, with 4-((1-hydroxy-4,5-dihydro-1H-imidazol-2-yl)amino)-N-(4-((1-hydroxy-4,5-dihydro-1H-imidazol-2-yl)amino)phenyl)benzamide (14d) showing 100% cures in the first-stage disease, while 15d, 16d, and 17d appeared to slightly improve survival. In addition, 14d showed weak activity in the chronic model of central nervous system infection in mice. No evidence of reduction of this compound with hepatic microsomes and mitochondria was found in vitro, suggesting that N-hydroxy imidazolines are metabolically stable and have intrinsic activity against T. brucei. In contrast to its unsubstituted parent compound, the uptake of 14d in T. brucei was independent of known drug transporters (i.e., T. brucei AT1/P2 and HAPT), indicating a lower predisposition to cross-resistance with other diamidines and arsenical drugs. Hence, the N-hydroxy bisimidazolines (14d in particular) represent a new class of promising antitrypanosomal agents. |
| Databáze: | OpenAIRE |
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