Title
Repositioning antitubercular 6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazoles for neglected tropical diseases : structure-activity studies on a preclinical candidate for visceral leishmaniasis Repositioning antitubercular 6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazoles for neglected tropical diseases : structure-activity studies on a preclinical candidate for visceral leishmaniasis
Author
Faculty/Department
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences. Pharmacy
Publication type
article
Publication
Washington, D.C. ,
Subject
Chemistry
Pharmacology. Therapy
Source (journal)
Journal of medicinal chemistry. - Washington, D.C., 1963, currens
Volume/pages
59(2016) :6 , p. 2530-2550
ISSN
0022-2623
ISI
000372946500019
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
Abstract
6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole derivatives were initially studied for tuberculosis within a backup program for the clinical trial agent pretomanid (PA-824). Phenotypic screening of representative examples against kinetoplastid diseases unexpectedly led to the identification of DNDI-VL-2098 as a potential first-in-class drug candidate for visceral leishmaniasis (VL). Additional work was then conducted to delineate its essential structural features, aiming to improve solubility and safety without compromising activity against VL. While the 4-nitroimidazole portion was specifically required, several modifications to the aryloxy side chain were well-tolerated e.g., exchange of the linking oxygen for nitrogen (or piperazine), biaryl extension, and replacement of phenyl rings by pyridine. Several less lipophilic analogues displayed improved aqueous solubility, particularly at low pH, although stability toward liver microsomes was highly variable. Upon evaluation in a mouse model of acute Leishmania donovani infection, one phenylpyridine derivative (37) stood out, providing efficacy surpassing that of the original preclinical lead.
E-info
https://repository.uantwerpen.be/docman/iruaauth/41c5dd/132115.pdf
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