Discovery of 4-((1-(1H-imidazol-2-yl)alkoxy)methyl)pyridines as a new class of Trypanosoma cruzi growth inhibitors. Issue 8 (15th April 2020)

• Record Type: Journal Article
• Authors: Ponzi, Simona; Bresciani, Alberto; Kaiser, Marcel; Nardi, Valentina; Nizi, Emanuela; Ontoria, Jesus M.; Pace, Paola; Paonessa, Giacomo; Summa, Vincenzo; Harper, Steven
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 8(2020)
• Publication Date: 2020-04-15
• Subjects: Trypanosoma cruzi -- Chagas disease -- Anti-parasitic -- CYP51 inhibitor -- 4-((1-(1H-imidazol-2-yl)alkoxy)methyl)pyridine; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127052
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: The identification of a new series of growth inhibitors of Trypanosoma cruzi, the causative agent of Chagas' disease, is described. In vitro screening of a subset of compounds from our in-house compound collection against the parasite led to the identification of hit compound 1 with low micromolar inhibition of T. cruzi growth. SAR exploration on the hit compound led to the identification of compounds that show nanomolar parasite growth inhibition (T. cruzi EC50 ≤ 100 nM) and no cytotoxicity in human cells (HeLa CC50 > 50 μM). Further investigation identified CYP51 inhibition (compound 11 CYP51 IC50 52 nM) as a possible mechanism of action of this new class of anti-parasitic agents.