合成恶二唑-2-氧化物衍生物作为针对 Schistosoma japonicum TGR 的潜在药物候选物。
Synthesis of oxadiazole-2-oxide derivatives as potential drug candidates for schistosomiasis targeting SjTGR.
机构信息
School of Life Science and Engineering, Southwest University of Science and Technology, Mianyang, 621010, China.
Marine College, Shandong University (Weihai), Weihai, 264209, China.
出版信息
Parasit Vectors. 2021 Apr 26;14(1):225. doi: 10.1186/s13071-021-04634-4.
BACKGROUND
Schistosomiasis is a chronic parasitic disease that affects millions of people's health worldwide. Because of the increasing drug resistance to praziquantel (PZQ), which is the primary drug for schistosomiasis, developing new drugs to treat schistosomiasis is crucial. Oxadiazole-2-oxides have been identified as potential anti-schistosomiasis reagents targeting thioredoxin glutathione reductase (TGR).
METHODS
In this work, one of the oxadiazole-2-oxides derivatives furoxan was used as the lead compound to exploit a series of novel furoxan derivatives for studying inhibitory activity against both recombinant Schistosoma japonicum TGR containing selenium (rSjTGR-Sec) and soluble worm antigen protein (SWAP) containing wild-type Schistosoma japonicum TGR (wtSjTGR), in order to develop a new leading compound for schistosomiasis. Thirty-nine novel derivatives were prepared to test their activity toward both enzymes. The docking method was used to detect the binding site between the active molecule and SjTGR. The structure-activity relationship (SAR) of these novel furoxan derivatives was preliminarily analyzed.
RESULTS
It was found that several new derivatives, including compounds 6a-6d, 9ab, 9bd and 9be, demonstrated greater activity toward rSjTGR-Sec or SWAP containing wtSjTGR than did furoxan. Interestingly, all intermediates bearing hydroxy (6a-6d) showed excellent inhibitory activity against both enzymes. In particular, compound 6d with trifluoromethyl on a pyridine ring was found to have much higher inhibition toward both rSjTGR-Sec (half-maximal inhibitory concentration, IC,7.5nM) and SWAP containing wtSjTGR (IC 55.8nM) than furoxan. Additionally, the docking method identified the possible matching sites between 6d and Schistosoma japonicum TGR (SjTGR), which theoretically lends support to the inhibitory activity of 6d.
CONCLUSION
The data obtained herein showed that 6d with trifluoromethyl on a pyridine ring could be a valuable leading compound for further study.
背景
血吸虫病是一种影响全球数百万人健康的慢性寄生虫病。由于吡喹酮（PZQ）的耐药性不断增加，吡喹酮是治疗血吸虫病的主要药物，因此开发治疗血吸虫病的新药至关重要。恶二唑-2-氧化物已被确定为针对硫氧还蛋白-谷胱甘肽还原酶（TGR）的潜在抗血吸虫病试剂。
方法
在这项工作中，恶二唑-2-氧化物衍生物中的一个呋咱被用作先导化合物，以开发一系列新型呋咱衍生物，用于研究对含硒重组日本血吸虫 TGR（rSjTGR-Sec）和含野生型日本血吸虫 TGR 的可溶性虫抗原蛋白（SWAP）的抑制活性，以便开发一种治疗血吸虫病的新先导化合物。为了测试它们对两种酶的活性，共制备了 39 种新型衍生物。使用对接方法检测活性分子与 SjTGR 之间的结合位点。初步分析了这些新型呋咱衍生物的构效关系（SAR）。
结果
发现包括化合物 6a-6d、9ab、9bd 和 9be 在内的几种新型衍生物对 rSjTGR-Sec 或含 wtSjTGR 的 SWAP 的活性均高于呋咱。有趣的是，所有带有羟基的中间体（6a-6d）对两种酶均显示出极好的抑制活性。特别是，在吡啶环上带有三氟甲基的化合物 6d 对 rSjTGR-Sec（半最大抑制浓度，IC，7.5nM）和含 wtSjTGR 的 SWAP（IC 55.8nM）的抑制作用均明显高于呋咱。此外，对接方法确定了 6d 与日本血吸虫 TGR（SjTGR）之间可能的匹配位点，这从理论上支持了 6d 的抑制活性。
结论
本文获得的数据表明，在吡啶环上带有三氟甲基的 6d 可能是进一步研究的有价值的先导化合物。
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