Department of Pharmaceutical Chemistry, Byers Hall, University of California San Francisco, 1700 4th Street, San Francisco, California 94158, United States.
J Med Chem. 2010 Nov 11;53(21):7852-63. doi: 10.1021/jm101015z.
We investigated a series of sulfonamide boronic acids that resulted from the merging of two unrelated AmpC β-lactamase inhibitor series. The new boronic acids differed in the replacement of the canonical carboxamide, found in all penicillin and cephalosporin antibiotics, with a sulfonamide. Surprisingly, these sulfonamides had a highly distinct structure-activity relationship from the previously explored carboxamides, high ligand efficiencies (up to 0.91), and K(i) values down to 25 nM and up to 23 times better for smaller analogues. Conversely, K(i) values were 10-20 times worse for larger molecules than in the carboxamide congener series. X-ray crystal structures (1.6-1.8 Å) of AmpC with three of the new sulfonamides suggest that this altered structure-activity relationship results from the different geometry and polarity of the sulfonamide versus the carboxamide. The most potent inhibitor reversed β-lactamase-mediated resistance to third generation cephalosporins, lowering their minimum inhibitory concentrations up to 32-fold in cell culture.
我们研究了一系列磺酰胺硼酸，这些硼酸是将两个不相关的 AmpCβ-内酰胺酶抑制剂系列合并而成的。这些新的硼酸在取代所有青霉素和头孢菌素抗生素中都存在的经典羧酰胺方面有所不同，用磺酰胺取代。令人惊讶的是，这些磺酰胺与之前探索的羧酰胺具有高度不同的结构-活性关系，配体效率高（高达 0.91），K(i)值低至 25 nM，对于较小的类似物，活性提高了 23 倍。相反，对于较大的分子，K(i)值比在羧酰胺同类物系列中差 10-20 倍。与三种新磺酰胺的 AmpC 的 X 射线晶体结构（1.6-1.8 Å）表明，这种改变的结构-活性关系是由于磺酰胺与羧酰胺的不同几何形状和极性所致。最有效的抑制剂逆转了β-内酰胺酶介导的对第三代头孢菌素的耐药性，使它们在细胞培养中的最低抑菌浓度降低了 32 倍。
