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首页> 外文期刊>Pharmaceuticals >Design, Synthesis, Experimental and Theoretical Characterization of a New Multitarget 2-Thienyl- N -Acylhydrazone Derivative
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Design, Synthesis, Experimental and Theoretical Characterization of a New Multitarget 2-Thienyl- N -Acylhydrazone Derivative

机译：一种新型多目标2-噻吩基-N-酰基Ac衍生物的设计，合成，实验和理论表征

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摘要

Pulmonary arterial hypertension (PAH) is a chronic cardiovascular disease that displays inflammatory components, which contributes to the difficulty of adequate treatment with the available therapeutic arsenal. In this context, the N -acylhydrazone derivative LASSBio-1359 was previously described as a multitarget drug candidate able to revert the events associated with the progression of PAH in animal models. However, in spite of having a dual profile as PDE4 inhibitor and adenosine A 2A receptor agonist, LASSBio-1359 does not present balanced potencies in the modulation of these two targets, which difficult its therapeutic use. In this paper, we describe the design concept of LASSBio-1835, a novel structural analogue of LASSBio-1359, planned by exploiting ring bioisosterism. Using X-ray powder diffraction, calorimetric techniques, and molecular modeling, we clearly indicate the presence of a preferred synperiplanar conformation at the amide function, which is fixed by an intramolecular 1,5-N???S σ-hole intramolecular interaction. Moreover, the evaluation of LASSBio-1835 ( 4 ) as a PDE4 inhibitor and as an A 2A agonist confirms it presents a more balanced dual profile, being considered a promising prototype for the treatment of PAH.
机译：肺动脉高压（PAH）是一种慢性心血管疾病，显示出炎症成分，导致难以使用可用的治疗性武器进行适当治疗。在这种情况下，N-酰基hydr衍生物LASSBio-1359先前被描述为能够在动物模型中还原与PAH进程相关的事件的多靶点候选药物。但是，尽管具有作为PDE4抑制剂和腺苷A 2A受体激动剂的双重特征，但LASSBio-1359在调节这两个靶标方面并未表现出平衡的效能，这使其治疗用途困难。在本文中，我们描述了LASSBio-1835的设计概念，这是LASSBio-1359的一种新型结构类似物，是通过利用环生物等排体规划的。使用X射线粉末衍射，量热技术和分子模型，我们清楚地表明在酰胺官能团上存在优选的间平面构象，该构象由分子内的1，5-N 18 Sσ孔分子内相互作用固定。此外，对LASSBio-1835（4）作为PDE4抑制剂和A 2A激动剂的评估证实，它具有更平衡的双重特性，被认为是治疗PAH的有希望的原型。

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