1,2,3-Triazolylmethaneboronate: A Structure Activity Relationship Study of a Class of β-Lactamase Inhibitors against Acinetobacter baumannii Cephalosporinase
1,2,3-Triazolylmethaneboronate: A Structure Activity Relationship Study of a Class of β-Lactamase Inhibitors against Acinetobacter baumannii Cephalosporinase
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DOI：
10.1021/acsinfecdis.0c00254
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发表时间：
2020-07-10
影响因子：
5.3
通讯作者：
Prati, Fabio
中科院分区：
文献类型：
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作者：
Caselli, Emilia;Fini, Francesco;Prati, Fabio
硼酸过渡态抑制剂（BATSIs）是已知的丝氨酸-内酰胺酶的可逆共价抑制剂。具有酰胺侧链和β -内酰胺侧链的特异性batsi的选择性和高效力是一种已建立和公认的合成策略。在这里，我们描述了一类新的batsi，其中酰胺基团被生物等异体三唑取代；这些化合物被设计为分子探针。为此，我们合成了26个α -三唑基甲基硼酸文库，并对临床有关不动杆菌源性头孢菌素酶ADC-7进行了检测。在稳态分析中，这些化合物的K-i值范围为90 nM至38 μ M（+/- 10%）。5个化合物与ADC-7 β -内酰胺酶配合结晶，晶体结构均显示三唑位于推定的酰胺结合位点，从而证实了三唑与酰胺的生物等构关系。这些新抑制剂作为原型支架的容易合成途径允许插入广泛的化学基团，能够探索酶结合位点，并提供对识别和催化中特定残基重要性的见解。发现的最佳抑制剂是化合物6q (K, 90 nM)，它在Arg340附近放置了一个托利基，使阳离子- π相互作用更有利。值得注意的是，除了降低头孢他啶对三种表达C类β -内酰胺酶的细菌菌株的最低抑制浓度（MIC）外，6q的结构与β -内酰胺酶的天然底物不相似，但却显示出明显的抑制活性。总之，这些观察结果验证了-三唑基硼酸是进一步设计抑制剂的有希望的模板。
Boronic acid transition state inhibitors (BATSIs) are known reversible covalent inhibitors of serine beta-lactamases. The selectivity and high potency of specific BATSIs bearing an amide side chain mimicking the beta-lactam's amide side chain are an established and recognized synthetic strategy. Herein, we describe a new class of BATSIs where the amide group is replaced by a bioisostere triazole; these compounds were designed as molecular probes. To this end, a library of 26 alpha-triazolylmethaneboronic acids was synthesized and tested against the clinically concerning Acinetobacter-derived cephalosporinase, ADC-7. In steady state analyses, these compounds demonstrated K-i values ranging from 90 nM to 38 mu M (+/- 10%). Five compounds were crystallized in complex with ADC-7 beta-lactamase, and all the crystal structures reveal the triazole is in the putative amide binding site, thus confirming the triazole-amide bioisosterism. The easy synthetic access of these new inhibitors as prototype scaffolds allows the insertion of a wide range of chemical groups able to explore the enzyme binding site and provides insights on the importance of specific residues in recognition and catalysis. The best inhibitor identified, compound 6q (K, 90 nM), places a tolyl group near Arg340, making favorable cation-pi interactions. Notably, the structure of 6q does not resemble the natural substrate of the beta-lactamase yet displays a pronounced inhibition activity, in addition to lowering the minimum inhibitory concentration (MIC) of ceftazidime against three bacterial strains expressing class C beta-lactamases. In summary, these observations validate the alpha-triazolylboronic acids as a promising template for further inhibitor design.