Pyridyl Benzamides as a Novel Class of Potent Inhibitors for the Kinetoplastid Trypanosoma brucei
2014 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 57, no 15, 6393-6402 p.Article in journal (Refereed) Published
A whole-organism screen of approximately 87000 compounds against Trypanosoma brucei brucei identified a number of promising compounds for medicinal chemistry optimization. One of these classes of compounds we termed the pyridyl benzamides. While the initial hit had an IC50 of 12 mu M, it was small enough to be attractive for further optimization, and we utilized three parallel approaches to develop the structure-activity relationships. We determined that the physicochemical properties for this class are generally favorable with particular positions identified that appear to block metabolism when substituted and others that modulate solubility. Our most active compound is 79, which has an IC50 of 0.045 mu M against the human pathogenic strain Trypanosoma brucei rhodesiense and is more than 4000 times less active against the mammalian L6 cell line.
Place, publisher, year, edition, pages
2014. Vol. 57, no 15, 6393-6402 p.
IdentifiersURN: urn:nbn:se:uu:diva-232603DOI: 10.1021/jm500191uISI: 000340445900010OAI: oai:DiVA.org:uu-232603DiVA: diva2:749300