苯磺酰胺类化合物的合成与碳酸酐酶抑制活性的评价

Design,synthesis and evaluation of benzene sulfonamide derivatives as potent carbonic anhydrase inhibitors

目的设计合成含苯并咪唑结构的苯磺酰胺类化合物,并评价化合物对人碳酸酐酶(hCA)Ⅰ、Ⅱ、Ⅸ的抑制活性,分析构效关系,获得具有潜在靶点选择性的先导化合物。方法分别以4-氟-3-硝基苯甲酸、3-氟-4-硝基苯甲酸为起始原料,经缩合、取代、硝基还原、环合反应生成目标化合物;采用人碳酸酐酶催化4-硝基邻苯二甲酸转化为4-硝基邻苯二甲酸根原理,利用酶标仪测定并计算化合物对酶的抑制活性。结果与结论共合成了30个目标化合物,其结构经质谱及核磁共振谱确证。体外抑制活性表明,与hCAⅨ相比,该类化合物具有较好的hCAⅠ/Ⅱ双靶点选择性,与阳性对照乙酰唑胺相比,化合物A6b、A6d、B6i的双靶点抑制作用佳,值得进一步进行体内药效、毒性研究。

Acute mountain sickness(AMS)affects approximately 25%-50%of newcomers to high altitudes above 2400 meters above sea level.Two human carbonic anhydrase isoforms,hCA I andⅡ,play key roles in developing high altitude illnesses.Hence,developing potent dual hCAⅠ/Ⅱinhibitors for prevention and treatment of AMS is a critical medical requirement.In this study,thirty benzene-sulfonamide derivatives(A6 a-A6 o,B6 a-B6 o)containing benzimidazole were synthesized and evaluated their inhibitory activity against these two isoforms.The target compounds were synthesized from 4-fluoro-3-nitrobenzoic acid or 3-fluoro-4-nitrobenzoic acid by condensation,substitution,nitro reduction and cyclization.Human carbonic anhydrases inhibitory activities were measured to catalyze the conversion of 4-nitrophthalic acid to 4-nitrophthalic acid.The newly designed compounds A6 b,A6 d and B6 i possessed the desired inhibitory activities.Their hCA I inhibitory capacities were 7.54 to 24.89-fold stronger than that of AAZ.