Fig. 2: Optimisation of the CTCB series of inhibitors of TbPFK.
IC50 values (µM) for inhibition of T. brucei phosphofructokinase. EC50 values (µM) for in vitro parasite killing of the bloodstream form of T. brucei strain Lister 427 (see Supplementary Methods 2.1 and 4.2). L.E. ligand efficiency. IC50 values are based on at least three independent measurements (‘biological replicates’). EC50 values were initially determined from two technical replicates. Estimated standard deviations (ESDs) for selected compounds were determined using biological replicate studies (n ≥ 3). The pKa values were calculated using ChemAxon software and categorised assuming physiological pH of 7.8 (Supplementary Table 6). The figure shows that there is a better translation from IC50 to EC50 for the more basic molecules. a The path to identifying the chemical scaffold used for lead compound development CTCB-001, the starting point for this work, was identified from a high-throughput screen as a good enzyme inhibitor but with poor trypanocidal activity10. b Inhibition data for derivatives of the pyrrolopyridine series. Details of the synthesis and characterisation of CTCB-405, CTCB-470 and CTCB-508 are given in Supplementary Methods 7 and 8. Source data for IC50 and EC50 values are provided as a Source Data File.
