Cunha Anna C, Figueiredo Juliana M, Tributino Jorge L M, Miranda Ana L P, Castro Helena C, Zingali Russolina B, Fraga Carlos A M, de Souza Maria Cecília B V, Ferreira Vitor F, Barreiro Eliezer J
Laboratório de Avaliação e Síntese de Substâncias Biotivas (LASSBio), Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, PO Box 68006, 21944-971, Rio de Janeiro, RJ, Brazil.
Bioorg Med Chem. 2003 May 1;11(9):2051-9. doi: 10.1016/s0968-0896(03)00055-5.
This paper describes the design, synthesis and pharmacological evaluation of new N-acylhydrazone (NAH) compounds, belonging to the N-substituted-phenyl-1,2,3-triazole-4-acylhydrazone class (2a-p). Classical heteroaromatic ring bioisosterism strategies were applied to the previously reported N-phenylpyrazolyl-4-acylhydrazone derivative 1, elected as lead-compound due to its important anti-aggregating profile on arachidonic acid induced platelet aggregation (IC(50)=24+/-0.5 micro M), from which emerge this new series 2. These new compounds 2a-p were readily synthesized, characterized and tested on platelet aggregation assays induced by collagen (5 micro g/mL), ADP (5 micro M) and arachidonic acid (100 micro M) in rabbit citrated platelet-rich plasma. Compounds 2b, 2d, and 2h were found to be the most potent, exhibiting a significant antiplatelet activity on arachidonic acid- and collagen-induced platelet aggregation. In addition, these new antiplatelet agents are free of gastric ulcerogenic effect and presented discrete anti-inflammatory and analgesic properties. The N-para-chlorophenyltriazolyl-4-acylhydrazone compound 2h produced the highest inhibitory effect on collagen (IC(50)=21.6+/-0.4 micro M) and arachidonic acid-induced platelet aggregation (IC(50)=2.2+/-0.06 micro M), suggesting that the nature of the substituent on the phenyl ring of the N-heteroaromatic system of NAH moiety may be an important structural requirement for the improvement of antiplatelet activity, in comparison with lead-series 1.
本文描述了新型N-酰腙（NAH）化合物的设计、合成及药理学评价，这些化合物属于N-取代苯基-1,2,3-三唑-4-酰腙类（2a-p）。经典的杂芳环生物电子等排体策略应用于先前报道的N-苯基吡唑基-4-酰腙衍生物1，因其对花生四烯酸诱导的血小板聚集具有重要的抗聚集活性（IC(50)=24±0.5 μM）而被选为先导化合物，由此衍生出了新的系列2。这些新化合物2a-p易于合成、表征，并在兔枸橼酸化富血小板血浆中进行了胶原（5 μg/mL）、ADP（5 μM）和花生四烯酸（100 μM）诱导的血小板聚集试验。发现化合物2b、2d和2h活性最强，对花生四烯酸和胶原诱导的血小板聚集表现出显著的抗血小板活性。此外，这些新型抗血小板药物无致胃溃疡作用，并具有一定的抗炎和镇痛特性。N-对氯苯基三唑基-4-酰腙化合物2h对胶原（IC(50)=21.6±0.4 μM）和花生四烯酸诱导的血小板聚集（IC(50)=2.2±0.06 μM）产生了最高的抑制作用，这表明与先导系列1相比，NAH部分N-杂芳环系统苯环上取代基的性质可能是提高抗血小板活性的重要结构要求。
