Structure-Activity relationships of replacements for the triazolopyridazine of Anti-Cryptosporidium lead SLU-2633.
Structure-Activity relationships of replacements for the triazolopyridazine of Anti-Cryptosporidium lead SLU-2633.
复制标题
抗隐孢子虫先导物 SLU-2633 的三唑并哒嗪替代物的构效关系。
DOI：
10.1016/j.bmc.2023.117295
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发表时间：
2023
影响因子：
3.5
通讯作者：
Meyers,MarvinJ
中科院分区：
文献类型：
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作者：
Oboh,Edmund;Teixeira,JoséE;Schubert,TannerJ;Maribona,AdrianaS;Denman,BrylonN;Patel,Radhika;Huston,ChristopherD;Meyers,MarvinJ
隐孢子虫病是一种传染性疾病，对儿童和免疫功能低下的人特别有害。感染是由寄生虫隐孢子虫引起的，严重时会导致脱水、营养不良和死亡。硝唑尼特是FDA唯一批准的药物，但对儿童仅适度有效，对免疫功能低下的患者无效。为了解决这一未满足的医疗需求，我们先前确定了三唑并哒嗪SLU-2633对隐孢子虫有效，EC 50为0.17 µM。在本研究中，我们开发了结构活性关系（SAR）的三唑并哒嗪头部基团的替代，探索不同的杂芳基基团的目的是保持效力，同时降低亲和力的hERG通道。合成了64种新的SLU-2633类似物，并测定了其相对于C的效力。小的发现最有效的化合物7，8-二氢-[1，2，4]三唑并[4，3-B]哒嗪17 a的CpEC 50为1.2 µM，比SLU-2633的效力低7倍，但具有改善的亲脂效率（LipE）评分。17 a在hERG膜片钳试验中发现，相对于10 µM的SLU-2633，3 H]-多非利特竞争性结合测定。虽然大多数其他杂环化合物的效力明显低于先导化合物，但一些类似物（如azabenzothiazole 31 b）在低微摩尔范围内具有良好的效力，类似于药物硝唑尼特，并代表了潜在的新先导化合物。总的来说，这项工作突出了末端杂环头部基团的重要作用，并代表了这类抗隐孢子虫化合物的SAR的理解的显着扩展。
Cryptosporidiosis is a diarrheal disease particularly harmful to children and immunocompromised people. Infection is caused by the parasite Cryptosporidium and leads to dehydration, malnutrition, and death in severe cases. Nitazoxanide is the only FDA approved drug but is only modestly effective in children and ineffective in immunocompromised patients. To address this unmet medical need, we previously identified triazolopyridazine SLU-2633 as potent against Cryptosporidium parvum, with an EC50of 0.17 µM. In the present study, we develop structure–activity relationships (SAR) for the replacement of the triazolopyridazine head group by exploring different heteroaryl groups with the aim of maintaining potency while reducing affinity for the hERG channel. 64 new analogs of SLU-2633 were synthesized and assayed for potency versusC. parvum. The most potent compound, 7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine17a, was found to have aCpEC50of 1.2 µM, 7-fold less potent than SLU-2633 but has an improved lipophilic efficiency (LipE) score.17awas found to decrease inhibition in an hERG patch-clamp assay by about two-fold relative to SLU-2633 at 10 µM despite having similar inhibition in a [3H]-dofetilide competitive binding assay. While most other heterocycles were significantly less potent than the lead, some analogs such as azabenzothiazole31b, have promising potency in the low micromolar range, similar to the drug nitazoxanide, and represent potential new leads for optimization. Overall, this work highlights the important role of the terminal heterocyclic head group and represents a significant extension of the understanding of the SAR for this class of anti-Cryptosporidiumcompounds.