Department of Pharmaceutical Chemistry, L.M. College of Pharmacy, Navrangpura, Ahmedabad 380009, Gujarat, India; Division of Biological and Life Sciences, Ahmedabad University, Ahmedabad 380009, Gujarat, India.
Department of Pharmaceutical Chemistry, L.M. College of Pharmacy, Navrangpura, Ahmedabad 380009, Gujarat, India.
Bioorg Chem. 2018 Aug;78:258-268. doi: 10.1016/j.bioorg.2018.03.019. Epub 2018 Mar 27.
Interleukin-1β converting enzyme contributes in various inflammatory and autoimmune diseases by maturing pro-inflammatory cytokines IL-1β, IL-18 and IL-33. Therefore, inhibition caspase-1 may provide a potential therapeutic strategy for the treatment of chronic inflammatory diseases. Here we have reported structure-based design, synthesis and biological evaluation of 2,4-diaminopyrimidine derivatives (6a-6w) as potential caspase-1 inhibitors. Six compounds 6m, 6n, 6o, 6p, 6q and 6r showed significant enzymatic inhibition with IC ranging from 0.022 to 0.078 µM. These compounds also displayed excellent cellular potency at sub-micromolar concentration. Moreover, molecular docking studies provided the useful binding insights specific for caspase-1 inhibition. All these results indicated that compounds 6m, 6n and 6o could be potential leads for the development of newer caspase-1 inhibitors as anti-inflammatory agents.
白细胞介素-1β转化酶通过成熟促炎细胞因子 IL-1β、IL-18 和 IL-33，参与多种炎症和自身免疫性疾病。因此，抑制半胱天冬酶-1可能为治疗慢性炎症性疾病提供一种潜在的治疗策略。在这里，我们报告了基于结构的设计、合成和生物评价 2,4-二氨基嘧啶衍生物（6a-6w）作为潜在的半胱天冬酶-1 抑制剂。6 种化合物 6m、6n、6o、6p、6q 和 6r 表现出显著的酶抑制活性，IC 范围为 0.022 至 0.078 µM。这些化合物在亚微摩尔浓度下也表现出优异的细胞效力。此外，分子对接研究提供了针对半胱天冬酶-1 抑制的有用结合见解。所有这些结果表明，化合物 6m、6n 和 6o 可能是开发新型半胱天冬酶-1 抑制剂作为抗炎剂的潜在先导化合物。
