Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Padova, Via Marzolo 5, 35131 Padova, Italy.
Eur J Med Chem. 2012 Feb;48:275-83. doi: 10.1016/j.ejmech.2011.12.026. Epub 2011 Dec 23.
A series of 3-phenyl-2,7-dihydro-1H-pyrrolo[3,2-f]quinazolin-1-one derivatives (3-PPyQZ) was synthesized starting from 5-amino-indoles, via condensation with N-ethoxycarbonylthiobenzamides followed by thermal cyclization. On the basis of their structural analogy with reported anti-thrombin pyrroloquinazolines, the derivatives were first tested for their capacity to inhibit platelet aggregation. Some of them had in vitro inhibitory effects on collagen and thrombin-induced aggregation in the micromolar range, and much higher inhibition than that shown by some phenyl-pyrroloquinolinones. Experiments to determine the mechanism of action of the most potent inhibitor (compound 18) indicated that it acts in at least two sites: one preceding the agonist-induced increase of cytosolic [Ca(2+)], and one following this step of the platelet activation cascade. The compound also inhibited thrombin-evoked protein-Tyr-phosphorylation. Although it is premature to draw definitive conclusions, the present results indicate that 3-PPyQZ structure, with the quite potent inhibitor of platelet aggregation compound 18, might constitute a starting point for the synthesis of potential anti-thrombosis agents.
从 5-氨基吲哚出发，通过与 N-乙氧羰基硫代苯甲酰胺缩合，然后热环化，合成了一系列 3-苯基-2,7-二氢-1H-吡咯并[3,2-f]喹唑啉-1-酮衍生物（3-PPyQZ）。基于它们与报道的抗凝血吡咯并喹唑啉类似的结构，首先测试了这些衍生物抑制血小板聚集的能力。其中一些在体外对胶原和凝血酶诱导的聚集具有微摩尔范围内的抑制作用，并且比一些苯并吡咯喹啉酮的抑制作用高得多。对最有效抑制剂（化合物 18）作用机制的实验表明，它至少在两个部位起作用：一个在激动剂诱导的细胞浆[Ca(2+)]增加之前，一个在血小板激活级联的这一步之后。该化合物还抑制凝血酶诱导的蛋白-Tyr 磷酸化。尽管得出明确结论还为时过早，但目前的结果表明，3-PPyQZ 结构和具有较强血小板聚集抑制剂 18 的化合物可能成为合成潜在抗血栓药物的起点。
