ALS is a rare type of progressive neurological disease with unknown etiology. It results in the gradual degeneration and death of motor neurons responsible for controlling the voluntary muscles. Identification of mutations in the superoxide dismutase (SOD) 1 gene has been the most significant finding in ALS research. SOD1 abnormalities have been associated with both familial as well as sporadic ALS cases. SOD2 is a highly inducible SOD that performs in concurrence with SOD1 to detoxify ROS. Induction of SOD2 can be obtained through activation of NF-ҡBs. We previously reported that SRI-22819 increases NF-ҡB expression and activation in vitro, but it has poor ADME properties in general and has no oral bioavailability. Our initial studies were focused on direct modifications of SRI-22819. There were active compounds identified but no improvement in microsomal stability was observed. In this context, we focused on making more significant structural changes in the core of the molecule. Ataluren, an oxadiazole compound that promotes read-through and expression of dystrophin in patients with Duchenne muscular dystrophy, bears some structural similarity to SRI-22819. Thus, we synthesized a series of SRI-22819 and Ataluren (PTC124) hybrid compounds. Several compounds from this series exhibited improved activity, microsomal stability and lower calculated polar surface area (PSA). This manuscript describes the synthesis and biological evaluation of SRI-22819 analogs and its hybrid combination with Ataluren.

ALS是一种病因不明的罕见类型的进行性神经疾病。它导致负责控制自愿肌肉的运动神经元逐渐退化和死亡。对超氧化物歧化酶（SOD）1基因突变的鉴定是ALS研究中最重要的发现。SOD1异常与家族性和散发性ALS病例都有关系。SOD2是一种高度可诱导的SOD，与SOD1协同工作以解毒ROS。SOD2的诱导可以通过激活NF-DBs获得。我们先前曾报道SRI-22819在体外可增加NF-ҡB的表达和激活，但它的ADME性质通常很差，并且没有口服生物利用度。我们最初的研究集中在对SRI-22819的直接修改上。确定了活性化合物，但未观察到微粒体稳定性的改善。在这种情况下，我们专注于在分子核心上进行更重大的结构变化。Ataluren是一种恶二唑化合物，可促进Duchenne肌营养不良患者的通透性和肌营养不良蛋白的表达，与SRI-22819具有某些结构相似性。因此，我们合成了一系列SRI-22819和Ataluren（PTC124）杂化化合物。该系列中的几种化合物表现出更高的活性，微粒体稳定性和更低的计算极性表面积（PSA）。