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Design, synthesis, and biological evaluation of 4-methoxy-3-arylamido-N -(substitutedphenyl)benzamide derivatives as potential antiplatelet agents
Archiv der Pharmazie ( IF 5.1 ) Pub Date : 2019-12-06 , DOI: 10.1002/ardp.201900231
Xiujie Liu 1, 2 , Xin Chen 1, 2 , Kai Qiu 2 , Zhihao Zhang 2
Affiliation  

A series of 4‐methoxy‐3‐arylamido‐N‐(substitutedphenyl)benzamides 6a–u were designed according to the splicing principle of structural design in the medicinal chemistry theory and were synthesized in five steps: nitration, acylation, ammoniation, reduction, and secondary ammoniation. The structures of the target compounds were characterized and verified by infrared, 1H nuclear magnetic resonance (NMR), 13C NMR, and electron spray ionization spectroscopy. Their in vitro antiplatelet aggregation activities induced by adenosine diphosphate (ADP) or arachidonic acid (AA) were assessed by Born's method. The biological evaluation revealed that all compounds exhibited certain levels of activities in both of the antiplatelet aggregation assays; compounds 6c (IC50 = 3.84 μM) and 6f (IC50 = 3.12 μM) displayed the strongest antiplatelet aggregation activities in the ADP‐induced and AA‐induced assay, separately. Moreover, compounds that had stronger activities were chosen for cell toxicity testing via the cell counting kit‐8 assay. The results indicated that none of the compounds had obvious cell toxicity against L929 cells at the doses of 10 and 20 μM. It is worth pointing out that compound 6c showed the highest antiplatelet activity and the lowest cell toxicity. In general, 4‐methoxy‐3‐arylamido‐N‐(substitutedphenyl)benzamides have the potential to become a kind of safer and more effective antiplatelet agents.

中文翻译:

4-甲氧基-3-芳基酰胺-N-(取代苯基)苯甲酰胺衍生物作为潜在抗血小板药物的设计、合成和生物学评价

根据药物化学理论中结构设计的剪接原理,设计了一系列4-甲氧基-3-芳基酰胺-N-(取代苯基)苯甲酰胺6a-u,通过硝化、酰化、氨化、还原、和二次氨化。目标化合物的结构通过红外、1H核磁共振(NMR)、13C核磁共振和电子喷雾电离光谱进行表征和验证。它们由二磷酸腺苷 (ADP) 或花生四烯酸 (AA) 诱导的体外抗血小板聚集活性通过 Born 方法进行评估。生物学评估表明,所有化合物在两种抗血小板聚集试验中都表现出一定水平的活性;化合物 6c (IC50 = 3.84 μM) 和 6f (IC50 = 3。12 μM) 在 ADP 诱导和 AA 诱导的测定中分别显示出最强的抗血小板聚集活性。此外,通过细胞计数试剂盒-8 测定选择具有更强活性的化合物进行细胞毒性测试。结果表明,在 10 μM 和 20 μM 的剂量下,没有一种化合物对 L929 细胞具有明显的细胞毒性。值得指出的是,化合物6c显示出最高的抗血小板活性和最低的细胞毒性。总的来说,4-甲氧基-3-芳基酰胺-N-(取代苯基)苯甲酰胺类药物有可能成为一种更安全、更有效的抗血小板药物。结果表明,在 10 μM 和 20 μM 的剂量下,没有一种化合物对 L929 细胞具有明显的细胞毒性。值得指出的是,化合物6c显示出最高的抗血小板活性和最低的细胞毒性。总的来说,4-甲氧基-3-芳基酰胺-N-(取代苯基)苯甲酰胺类药物有可能成为一种更安全、更有效的抗血小板药物。结果表明,在 10 μM 和 20 μM 的剂量下,没有一种化合物对 L929 细胞具有明显的细胞毒性。值得指出的是,化合物6c显示出最高的抗血小板活性和最低的细胞毒性。总的来说,4-甲氧基-3-芳基酰胺-N-(取代苯基)苯甲酰胺类药物有可能成为一种更安全、更有效的抗血小板药物。
更新日期:2019-12-06
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