Covalent drugs with prolonged actions often show superior potency, yet integrated strategies for optimizing their structural and electronic features are lacking. Herein, we present our effort directed towards understanding the contribution of chemical reactivity to biological potency to rationally design new covalent inhibitors based on the ent-ladane andrographolide scaffold for anti-inflammatory action. Specifically, a series of andrographolide derivatives comprising various Michael acceptors was developed and their thiol reactivity was assayed under various chemical and biological conditions. The cell-based SAR studies permitted the assessment of the inhibitor efficacy in more complex systems, which were often limited in traditional covalent drug development using isolated proteins or peptides. Our in vitro study identified enone 17 as the most promising candidate which demonstrated potent anti-inflammatory activity and superior safety profiles as compared to the lead compound andrographolide. Its reversibility following a Michael addition reaction with biological thiols resulted in more predictable pharmacological responses. In addition, 17 exhibited good in vivo efficacy at doses as low as 0.3 mg/kg when tested in LPS-induced acute lung injury model. Given a good balance of chemical reactivity and biological potency, enone 17 potentially offers a new therapeutic option based on natural product chemistry for the management of inflammatory conditions.

具有延长作用的共价药物通常显示出优越的功效，但是缺乏优化其结构和电子特征的综合策略。在此，我们提出我们引向理解化学反应的贡献生物效价合理设计基础上，新的共价抑制剂努力耳鼻喉科-ladane穿心莲内酯支架的抗炎作用。具体而言，开发了包含各种迈克尔受体的一系列穿心莲内酯衍生物，并在各种化学和生物学条件下测定了它们的硫醇反应性。基于细胞的SAR研究允许在更复杂的系统中评估抑制剂的功效，这在使用分离的蛋白质或肽进行的传统共价药物开发中通常受到限制。我们的体外研究确定烯酮17是最有前途的候选药物，与铅类穿心莲内酯相比，它具有强大的抗炎活性和优越的安全性。其与生物硫醇的迈克尔加成反应后的可逆性导致更可预测的药理反应。另外，当在LPS诱导的急性肺损伤模型中进行测试时，有17种药物在低至0.3 mg / kg的剂量下表现出良好的体内功效。鉴于化学反应性和生物效能之间的良好平衡，烯酮17潜在地提供了基于天然产物化学的新治疗选择，可用于治疗炎症。