Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
Pharmacology Department, National Research Centre, Dokki, Giza 12622, Egypt.
Med Chem. 2021;17(2):171-186. doi: 10.2174/1573406416666200327191100.
Hypertension, one of the most common cardiovascular diseases that can cause coronary disease, stroke, myocardial infarction, and sudden death, it is the major contributor to cardiac failure as well as renal insufficiency.
As there are many cardio-active pyridazinone-base derivatives in clinical use, therefore, we aimed to synthesize a new series of pyridazin-3-ones and evaluate their vasorelaxant activity.
A new series of synthesized compounds were carried out first by the synthesis of 6- flouroarylpyridazinones by cyclization of 3-(4-flourobenzoyl) propionic acid with hydrazine hydrate or arylhydrazines to provide the corresponding pyridazinone derivatives 2a-d. Mannich reaction was performed using morpholine or piperidine formaldehyde to obtain compounds 3a,b. On the other hand, reaction of 2a with various chloroacetamide intermediates, in dimethylformamide and potassium carbonate as a catalyst, afforded the target compounds 5a-c. The aromatic acid hydrazide intermediates 6a-g were prepared in 50-90% yield, by reacting to the prepared esters with hydrazine hydrate under reflux in ethanol. The two compounds 8a,b were prepared via condensation of 7a,b with ethyl chloroacetate in dry acetone. Finally, the target 2,4,6-trisubstituted pyridazinones 9a-c derivatives were obtained by the reaction of 7a with the appropriate aromatic aldehyde or substituted acetophenones. The new compounds were then evaluated for their vasorelaxant properties using isolated thoracic rat aortic rings. In addition, a homology model was built and molecular modeling simulation of these compounds into the active sites of the newly created α1a-adrenoceptor model was performed in order to predict and rationalize their affinities toward this receptor.
Among these compounds; 5a was the most potent, it exhibited approximately two-times the activity of prazosin (IC50 = 0.250, 0.487 mmol, respectively) also, fourteen compounds were more potent than prazosin.
高血压是最常见的心血管疾病之一，可导致冠心病、中风、心肌梗死和猝死，也是心力衰竭和肾功能不全的主要原因。
由于临床上有许多具有心脏活性的哒嗪酮基衍生物，因此，我们旨在合成一系列新的哒嗪-3-酮类化合物，并评估它们的血管舒张活性。
首先通过 3-（4-氟苯甲酰基）丙酸与水合肼或芳基肼环化合成 6-氟芳基哒嗪酮，合成一系列新的合成化合物，得到相应的哒嗪酮衍生物 2a-d。用吗啉或哌啶甲醛进行Mannich 反应，得到化合物 3a，b。另一方面，2a 与各种氯乙酰胺中间体在二甲基甲酰胺和碳酸钾作为催化剂的条件下反应，得到目标化合物 5a-c。通过将制备的酯在乙醇中回流与水合肼反应，以 50-90%的产率制备了芳基酸酰肼中间体 6a-g。通过在干燥的丙酮中用氯乙酸乙酯缩合 7a，b 得到了两个化合物 8a，b。最后，通过 7a 与适当的芳醛或取代苯乙酮反应，得到了目标 2,4,6-三取代哒嗪酮 9a-c 衍生物。然后，使用分离的大鼠胸主动脉环评估新化合物的血管舒张特性。此外，构建了一个同源模型，并对这些化合物进行了分子建模模拟，进入新创建的α1a-肾上腺素受体模型的活性部位，以预测和合理化它们对该受体的亲和力。
在这些化合物中；5a 的活性最强，其活性约为哌唑嗪的两倍（IC50=0.250、0.487mmol，分别），还有 14 种化合物比哌唑嗪更有效。
