Discovery of 4-((1-(1H-imidazol-2-yl)alkoxy)methyl)pyridines as a new class of Trypanosoma cruzi growth inhibitors.

Simona Ponzi, Alberto Bresciani, Marcel Kaiser, Valentina Nardi, Emanuela Nizi, Jesus M Ontoria, Paola Pace, Giacomo Paonessa, Vincenzo Summa, Steven Harper

Bioorganic & medicinal chemistry letters 2020 Apr 15

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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. Copyright © 2020 Elsevier Ltd. All rights reserved.

Citation

Simona Ponzi, Alberto Bresciani, Marcel Kaiser, Valentina Nardi, Emanuela Nizi, Jesus M Ontoria, Paola Pace, Giacomo Paonessa, Vincenzo Summa, Steven Harper. Discovery of 4-((1-(1H-imidazol-2-yl)alkoxy)methyl)pyridines as a new class of Trypanosoma cruzi growth inhibitors. Bioorganic & medicinal chemistry letters. 2020 Apr 15;30(8):127052