Discovery of a Selective Series of Inhibitors of Plasmodium falciparum HDACs

Abstract

The identification of a new series of P. falciparum growth inhibitors is described. Starting from a series of known human class I HDAC inhibitors a SAR exploration based on growth inhibitory activity in parasite and human cells-based assays led to the identification of compounds with submicromolar inhibition of P. falciparum growth (EC50 < 500 nM) and good selectivity over the activity of human HDAC in cells (up to >50-fold). Inhibition of parasital HDACs as the mechanism of action of this new class of selective growth inhibitors is supported by hyperacetylation studies.

Keywords: 4-arylimidazoles; Malaria; PfHDAC1; Plasmodium falciparum.

Figure 1

Structures of known human HDAC inhibitors.

Figure 2

Western Blot analysis of purified wt and Y301H mutant PfHDAC1s using anti-Flag, anti-hHDAC2, or anti-hHDAC1. Arrows indicate the position of the probed protein. M, molecular weight marker.

Scheme 1. Chemistry for SAR at Aryl Substituent

Reagents and conditions: (a) (i) MeNHOMe.HCl, HBTU, DIPEA, DMF, RT; (ii) LiAlH₄, THF, −20 °C; (iii) glyoxal, NH₃, MeOH, RT; (b) (i) NIS, CH₃CN, −10 °C; (ii) Na₂SO₃, Bu₄NHSO₄, dioxane–water, 160 °C, microwave, 30 min; (c) (i) TFA, DCM, RT; (ii) MeNH₂, HBTU, DMF, RT; (d) (i) HBr in AcOH, DCM, 0 °C to RT; (ii) thiazole-2-carboxylic acid, EDC.HCl, HOBt, DIPEA, DMF, RT; (e) ArB(OH)₂, PdCl₂(dppf), K₂CO₃, DME–water, 110 °C.