Title
|
|
|
|
7-Substituted 2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines : novel antitubercular agents lead to a new preclinical candidate for visceral leishmaniasis
| |
Author
|
|
|
|
| |
Abstract
|
|
|
|
Within a backup program for the clinical investigational agent pretomanid (PA-824), scaffold hopping from delamanid inspired the discovery of a novel class of potent antitubercular agents that unexpectedly possessed notable utility against the kinetoplastid disease visceral leishmaniasis (VL). Following the identification of delamanid analogue DNDI-VL-2098 as a VL preclinical candidate, this structurally related 7 substituted 2-nitro-5,6-dihydroimidazo [2,1-b][1,3]oxazine class was further explored, seeking efficacious backup compounds with improved solubility and safety. Commencing with a biphenyl lead, bioisosteres formed by replacing one phenyl by pyridine or pyrimidine showed improved solubility and potency, whereas more hydrophilic side chains reduced VL activity. In a Leishmania donovani mouse model, two racemic phenylpyridines (71 and 93) were superior, with the former providing >99% inhibition at 12.5 mg/kg (b.i.d., orally) in the Leishmania infantum hamster model. Overall, the 7R enantiomer of 71 (79) displayed more optimal efficacy, pharmacokinetics, and safety, leading to its selection as the preferred development candidate. |
| |
Language
|
|
|
|
English
| |
Source (journal)
|
|
|
|
Journal of medicinal chemistry. - Washington, D.C., 1963, currens
| |
Publication
|
|
|
|
Washington, D.C.
:
2017
| |
ISSN
|
|
|
|
0022-2623
[print]
1520-4804
[online]
| |
DOI
|
|
|
|
10.1021/ACS.JMEDCHEM.7B00034
| |
Volume/pages
|
|
|
|
60
:10
(2017)
, p. 4212-4233
| |
ISI
|
|
|
|
000402498200008
| |
Pubmed ID
|
|
|
|
28459575
| |
Full text (Publisher's DOI)
|
|
|
|
| |
Full text (publisher's version - intranet only)
|
|
|
|
| |
|