by Koovits PJ, Dessoy MA, Matheeussen A, Maes L, Caljon G, Mowbray CE, Kratz JM, Dias LC. Bioorganic & Medicinal Chemistry Letters 2019, doi: 10.1016/j.bmcl.2019.126779
Summary: There is a large unmet need for efficacious, safe, and affordable medicines active against Trypanosoma cruzi, the parasite responsible for Chagas disease. Drug candidates are needed whose mechanism of action differs from inhibition of CYP51. The authors present a 4-azaindole-2-piperidine compound selected from GlaxoSmithKline’s recently disclosed open-resource “Chagas box” that possesses moderate activity against T. cruzi and does not inhibit CYP51. The authors present a detailed investigation into the structure-activity relationship of this compound. Despite considerable medicinal chemistry efforts, a suitably potent and metabolically stable compound was not identified to advance the series into in vivo studies. Elucidation of the biological target of this series might enable a target-based drug discovery campaign and/or further rational optimization of this series.
