دورية أكاديمية
أعرض في EDS

7-Aryl-7-deazapurine 3'-deoxyribonucleoside derivative as a novel lead for Chagas' disease therapy: in vitro and in vivo pharmacology.

التفاصيل البيبلوغرافية
العنوان: 7-Aryl-7-deazapurine 3'-deoxyribonucleoside derivative as a novel lead for Chagas' disease therapy: in vitro and in vivo pharmacology.
المؤلفون: Cardoso-Santos C; Laboratory of Cellular Biology (LBC), Oswaldo Cruz Institute (IOC/FIOCRUZ), 21040-360 Rio de Janeiro, RJ, Brazil.; Laboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, 2610 Wilrijk, Antwerp, Belgium., Ferreira de Almeida Fiuza L; Laboratory of Cellular Biology (LBC), Oswaldo Cruz Institute (IOC/FIOCRUZ), 21040-360 Rio de Janeiro, RJ, Brazil., França da Silva C; Laboratory of Cellular Biology (LBC), Oswaldo Cruz Institute (IOC/FIOCRUZ), 21040-360 Rio de Janeiro, RJ, Brazil., Mazzeti AL; Laboratory of Cellular Biology (LBC), Oswaldo Cruz Institute (IOC/FIOCRUZ), 21040-360 Rio de Janeiro, RJ, Brazil., Donola Girão R; Laboratory of Cellular Biology (LBC), Oswaldo Cruz Institute (IOC/FIOCRUZ), 21040-360 Rio de Janeiro, RJ, Brazil., Melo de Oliveira G; Laboratory of Cellular Biology (LBC), Oswaldo Cruz Institute (IOC/FIOCRUZ), 21040-360 Rio de Janeiro, RJ, Brazil., da Gama Jaen Batista D; Laboratory of Cellular Biology (LBC), Oswaldo Cruz Institute (IOC/FIOCRUZ), 21040-360 Rio de Janeiro, RJ, Brazil., Cruz Moreira O; Real Time PCR Platform RPT09A, Laboratory of Molecular Biology and Endemic Diseases, Oswaldo Cruz Institute (IOC/FIOCRUZ), Rio de Janeiro, RJ, Brazil., Lins da Silva Gomes N; Real Time PCR Platform RPT09A, Laboratory of Molecular Biology and Endemic Diseases, Oswaldo Cruz Institute (IOC/FIOCRUZ), Rio de Janeiro, RJ, Brazil., Maes L; Laboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, 2610 Wilrijk, Antwerp, Belgium., Caljon G; Laboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, 2610 Wilrijk, Antwerp, Belgium., Hulpia F; Laboratory for Medicinal Chemistry (Campus Heymans), Ghent University, Ottergemsesteenweg 460, 9000 Gent, Belgium., Calenbergh SV; Laboratory for Medicinal Chemistry (Campus Heymans), Ghent University, Ottergemsesteenweg 460, 9000 Gent, Belgium., Correia Soeiro MN; Laboratory of Cellular Biology (LBC), Oswaldo Cruz Institute (IOC/FIOCRUZ), 21040-360 Rio de Janeiro, RJ, Brazil.
المصدر: JAC-antimicrobial resistance [JAC Antimicrob Resist] 2021 Nov 17; Vol. 3 (4), pp. dlab168. Date of Electronic Publication: 2021 Nov 17 (Print Publication: 2021).
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Oxford University Press Country of Publication: England NLM ID: 101765283 Publication Model: eCollection Cited Medium: Internet ISSN: 2632-1823 (Electronic) Linking ISSN: 26321823 NLM ISO Abbreviation: JAC Antimicrob Resist Subsets: PubMed not MEDLINE
أسماء مطبوعة: Original Publication: [Oxford] : Oxford University Press, [2019]-
مستخلص: Background: The protozoan Trypanosoma cruzi is auxotrophic for purines and causes Chagas' disease (CD), a neglected illness affecting >6 million people. Combining the 3-deoxyribofuranose part of cordycepin with the modified purine ring of a nucleoside 'hit' led to the discovery of 4-amino-5-(4-chlorophenyl)-N7-(3'-deoxy-β-d-ribofuranosyl)-pyrrolo[2,3-d]pyrimidine (Cpd 1 ), revealing promising anti- T. cruzi activity.
Objectives: To further evaluate Cpd 1   in vitro and in vivo to fully assess its therapeutic potential against CD, covering cell culture sterilization through washout assays, drug combination with benznidazole and long-term administration in T. cruzi -infected mice.
Results: Although less susceptible to Cpd 1 than amastigotes, trypomastigotes present an impaired capacity to successfully establish intracellular infection of cardiac cultures. Combination of benznidazole with Cpd 1 indicated no interaction (additive effect) (FIC index = 0.72) while administration to mice at one-tenth of the optimal dose (2.5 mg/kg and 10 mg/kg for Cpd 1 and benznidazole, respectively) suppressed parasitaemia but failed to avoid mortality. Long-term treatment (60 days) gave a rapid drop of the parasitaemia (>98% decline) and 100% mice survival but only 16% cure. In vitro washout experiments demonstrated that although parasite release into the supernatant of infected cardiac cultures was reduced by >94%, parasite recrudescence did occur after treatment.
Conclusions: Parasite recrudescence did occur after treatment corroborating the hypothesis of therapeutic failure due to subpopulations of dormant forms and/or genetic factors in persister parasites involved in natural drug resistance.
(© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)
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تواريخ الأحداث: Date Created: 20211122 Latest Revision: 20220428
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC8599808
DOI: 10.1093/jacamr/dlab168
PMID: 34806007
قاعدة البيانات: MEDLINE
الوصف
تدمد:2632-1823
DOI:10.1093/jacamr/dlab168