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目的设计合成新型2,4-二胺基喹唑啉类PAK4小分子抑制剂,并对其抑酶活性进行评价。方法以5-氯-2-氨基苯甲酸为起始原料,经环合反应、氯代反应、两次芳香亲核取代反应,制备5-氯-2,4-二胺基喹唑啉类目标化合物;以3,4-二甲氧基苯甲酸为起始原料,经硝化反应、还原反应、环合反应、两次芳香亲核取代反应,制备6,7-二甲氧基-2,4-二胺基喹唑啉类目标化合物。采用Kinase-Glo激酶发光法测试目标化合物对PAK4的体外抑酶活性。结果与结论合成了11个未见文献报道的新型2,4-二胺基喹唑啉类化合物,目标物的结构经MS和1H-NM R谱确证;体外抑酶活性评价结果表明,目标化合物对PAK4具有较好的抑制活性,IC50值均小于30μmol·L-1,其中,活性较好的两个化合物(5b、5d)IC50值分别是8.66、11.71μmol·L-1,具有进一步研究的价值。
OBJECTIVE To design and synthesize a novel 2,4-diaminoquinazoline PAK4 small molecule inhibitor and to evaluate its inhibitory activity. Methods Starting from 5-chloro-2-aminobenzoic acid, the target of 5-chloro-2,4-diaminoquinazoline was prepared by cyclization reaction, chlorination reaction and aromatic nucleophilic substitution reaction Compounds; 3,4-dimethoxybenzoic acid as a starting material, the nitration reaction, the reduction reaction, the cyclization reaction, two aromatic nucleophilic substitution reaction to prepare 6,7-dimethoxy-2,4 - Diaminoquinazol target compounds. The inhibitory activity of the target compounds against PAK4 in vitro was tested by Kinase-Glo kinase luminescence method. RESULTS AND CONCLUSION Eleven novel 2,4-diaminoquinazolines were synthesized and their structures were confirmed by MS and 1H-NMR spectra. The results of in vitro inhibition assay showed that the target compounds The inhibitory activity of PAK4 was better than that of IC50 of IC50, the IC50 values were less than 30μmol·L-1. IC50 values of the two active compounds (5b, 5d) were 8.66, 11.71μmol·L-1, respectively value.