Identification of Clinically Viable Quinolinol Inhibitors of Botulinum Neurotoxin A Light Chain

[Image: see text] Botulinum neurotoxins (BoNT) are the most potent toxins known and a significant bioterrorist threat. Few small molecule compounds have been identified that are active in cell-based or animal models, potentially due to toxin enzyme plasticity. Here we screened commercially available quinolinols, as well as synthesized hydroxyquinolines. Seventy-two compounds had IC(50) values below 10 μM, with the best compound exhibiting submicromolar inhibition (IC(50) = 0.8 μM). Structure–activity relationship trends showed that the enzyme tolerates various substitutions at R(1) but has a clear preference for bulky aryl amide groups at R(2), while methylation at R(3) increased inhibitor potency. Evaluation of the most potent compounds in an ADME panel showed that these compounds possess poor solubility at pH 6.8, but display excellent solubility at low pH, suggesting that oral dosing may be possible. Our data show the potential of quinolinol compounds as BoNT therapeutics due to their good in vitro potencies and favorable ADME properties.