Publication
Title
Revisiting tubercidin against kinetoplastid parasites : aromatic substitutions at position 7 improve activity and reduce toxicity
Author
Abstract
The nucleoside antibiotic tubercidin displays strong activity against different target organisms, but it is notoriously toxic to mammalian cells. However, the effects of tubercidin against T. brucei parasites inspired us to synthesize several C7 substituted analogs for in vitro evaluation, in order to find suitable hit compounds. C7 Deazaadenosines substituted with electron-poor phenyl groups were found to have micromolar activity against T. brucei in vitro. Replacement of the phenyl for a pyridine ring gave compound 13 with submicromolar potency and much-attenuated cytotoxicity compared to tubercidin. The veterinary pathogen T. congolense was equally affected by 13in vitro. Transporter studies in T. b. brucei indicated that 13 is taken up efficiently by both the P1 and P2 adenosine transporters, making the occurrence of transporter-related resistance and cross-resistance with diamidine drugs such as diminazene aceturate and pentamidine as well as with melaminophenyl arsenicals unlikely. Evaluation of the in vitro metabolic stability of analog 13 indicated that this analog was significantly metabolized in mouse microsomal fractions, precluding further in vivo evaluation in mouse models of HAT.
Language
English
Source (journal)
European journal of medicinal chemistry. - Paris, 1974, currens
Publication
Paris : 2019
ISSN
0223-5234
Volume/pages
164(2019), p. 689-705
ISI
000458221400045
Pubmed ID
30677668
Full text (Publisher's DOI)
Full text (open access)
Full text (publisher's version - intranet only)
UAntwerpen
Faculty/Department
Research group
Project info
Modified 7-deazapurine nucleoside analogues for the treatment of human African trypanosomiasis: towards a strong proof-of-concept.
Veterinary and human parasitology.
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identification
Creation 08.01.2019
Last edited 16.09.2021
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