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Design, Synthesis, and Evaluation of New Hybrid Derivatives of 5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one as Potential Dual Inhibitors of Blood Coagulation Factors Xa and XIa
Molecules ( IF 4.2 ) Pub Date : 2024-01-11 , DOI: 10.3390/molecules29020373 Anna A Skoptsova 1 , Athina Geronikaki 2 , Nadezhda P Novichikhina 1 , Alexey V Sulimov 3 , Ivan S Ilin 3 , Vladimir B Sulimov 3 , Georgii A Bykov 4 , Nadezhda A Podoplelova 5 , Oleg V Pyankov 6 , Khidmet S Shikhaliev 1
Molecules ( IF 4.2 ) Pub Date : 2024-01-11 , DOI: 10.3390/molecules29020373 Anna A Skoptsova 1 , Athina Geronikaki 2 , Nadezhda P Novichikhina 1 , Alexey V Sulimov 3 , Ivan S Ilin 3 , Vladimir B Sulimov 3 , Georgii A Bykov 4 , Nadezhda A Podoplelova 5 , Oleg V Pyankov 6 , Khidmet S Shikhaliev 1
Affiliation
Cardiovascular diseases caused by blood coagulation system disorders are one of the leading causes of morbidity and mortality in the world. Research shows that blood clotting factors are involved in these thrombotic processes. Among them, factor Xa occupies a key position in the blood coagulation cascade. Another coagulation factor, XIa, is also a promising target because its inhibition can suppress thrombosis with a limited contribution to normal hemostasis. In this regard, the development of dual inhibitors as new generation anticoagulants is an urgent problem. Here we report the synthesis and evaluation of novel potential dual inhibitors of coagulation factors Xa and XIa. Based on the principles of molecular design, we selected a series of compounds that combine in their structure fragments of pyrrolo[3,2,1-ij]quinolin-2-one and thiazole, connected through a hydrazine linker. The production of new hybrid molecules was carried out using a two-stage method. The reaction of 5,6-dihydropyrrolo[3,2,1-ij]quinoline-1,2-diones with thiosemicarbazide gave the corresponding hydrazinocarbothioamides. The reaction of the latter with DMAD led to the target methyl 2-(4-oxo-2-(2-(2-oxo-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1(2H)-ylidene)hydrazineyl)thiazol-5(4H)-ylidene)acetates in high yields. In vitro testing of the synthesized molecules revealed that ten of them showed high inhibition values for both the coagulation factors Xa and XIa, and the IC50 value for some compounds was also assessed. The resulting structures were also tested for their ability to inhibit thrombin.
中文翻译:
5,6-二氢-4H-吡咯并[3,2,1-ij]喹啉-2(1H)-one的新型杂交衍生物作为凝血因子Xa和XIa潜在双重抑制剂的设计、合成和评价
由凝血系统疾病引起的心血管疾病是世界上发病率和死亡率的主要原因之一。研究表明,凝血因子参与这些血栓形成过程。其中,因子 Xa 在凝血级联反应中占据关键位置。另一种凝血因子 XIa 也是一个很有前途的靶点,因为它的抑制可以抑制血栓形成,对正常止血的作用有限。在这方面,开发双重抑制剂作为新一代抗凝剂是一个紧迫的问题。在这里,我们报告了凝血因子 Xa 和 XIa 的新型潜在双重抑制剂的合成和评价。基于分子设计原理,我们选择了一系列化合物,这些化合物在其结构中结合了吡咯并[3,2,1-ij]喹啉-2-酮和噻唑,通过肼连接子连接。新的杂化分子的生产是使用两阶段方法进行的。5,6-二氢吡咯并[3,2,1-ij]喹啉-1,2-二酮与硫代氨基脲反应得到相应的肼基碳酰胺。后者与 DMAD 的反应导致目标甲基 2-(4-氧代-2-(2-(2-氧代-5,6-二氢-4H-吡咯并[3,2,1-ij]喹啉-1(2H)-亚基)肼酰基)噻唑-5(4H)-亚基)乙酸酯,产率高。合成分子的体外测试显示,其中 10 个分子对凝血因子 Xa 和 XIa 均显示出高抑制值,并且还评估了一些化合物的 IC50 值。还测试了所得结构抑制凝血酶的能力。
更新日期:2024-01-11
中文翻译:
5,6-二氢-4H-吡咯并[3,2,1-ij]喹啉-2(1H)-one的新型杂交衍生物作为凝血因子Xa和XIa潜在双重抑制剂的设计、合成和评价
由凝血系统疾病引起的心血管疾病是世界上发病率和死亡率的主要原因之一。研究表明,凝血因子参与这些血栓形成过程。其中,因子 Xa 在凝血级联反应中占据关键位置。另一种凝血因子 XIa 也是一个很有前途的靶点,因为它的抑制可以抑制血栓形成,对正常止血的作用有限。在这方面,开发双重抑制剂作为新一代抗凝剂是一个紧迫的问题。在这里,我们报告了凝血因子 Xa 和 XIa 的新型潜在双重抑制剂的合成和评价。基于分子设计原理,我们选择了一系列化合物,这些化合物在其结构中结合了吡咯并[3,2,1-ij]喹啉-2-酮和噻唑,通过肼连接子连接。新的杂化分子的生产是使用两阶段方法进行的。5,6-二氢吡咯并[3,2,1-ij]喹啉-1,2-二酮与硫代氨基脲反应得到相应的肼基碳酰胺。后者与 DMAD 的反应导致目标甲基 2-(4-氧代-2-(2-(2-氧代-5,6-二氢-4H-吡咯并[3,2,1-ij]喹啉-1(2H)-亚基)肼酰基)噻唑-5(4H)-亚基)乙酸酯,产率高。合成分子的体外测试显示,其中 10 个分子对凝血因子 Xa 和 XIa 均显示出高抑制值,并且还评估了一些化合物的 IC50 值。还测试了所得结构抑制凝血酶的能力。