Identification of clinically viable quinolinol inhibitors of botulinum neurotoxin A light chain.

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 IC50 values below 10 μM, with the best compound exhibiting submicromolar inhibition (IC50 = 0.8 μM). Structure–activity relationship trends showed that the enzyme tolerates various substitutions at R1 but has a clear preference for bulky aryl amide groups at R2, while methylation at R3 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.

肉毒神经毒素（BoNT）是已知毒性最强的毒素，也是一种重大的生物恐怖威胁。在基于细胞或动物的模型中具有活性的小分子化合物很少被发现，这可能是由于毒素酶的可塑性。在此，我们筛选了市售的喹啉醇以及合成的羟基喹啉。72种化合物的半数抑制浓度（IC50）值低于10 μM，其中最佳化合物表现出亚微摩尔级的抑制作用（IC50 = 0.8 μM）。构效关系趋势表明，该酶能耐受R1位置的各种取代基，但明显更倾向于R2位置的大体积芳基酰胺基团，而R3位置的甲基化可提高抑制剂的效力。对一组吸收、分布、代谢和排泄（ADME）特性最显著的化合物进行评估显示，这些化合物在pH值为6.8时溶解性较差，但在低pH值时溶解性极佳，这表明口服给药是可能的。我们的数据表明，喹啉醇化合物由于其良好的体外效力和有利的ADME特性，具有作为肉毒神经毒素治疗药物的潜力。