Díaz-Quiroz Dulce Catalina, Cardona-Félix César Salvador, Viveros-Ceballos José Luis, Reyes-González Miguel Angel, Bolívar Franciso, Ordoñez Mario, Escalante Adelfo
a Departamento de Ingeniería Celular y Biocatálisis , Instituto de Biotecnología, Universidad Nacional Autónoma de México , Cuernavaca , México.
b CONACyT - Instituto Politécnico Nacional, Centro Interdisciplinario de Ciencias Marinas , La Paz , México.
J Enzyme Inhib Med Chem. 2018 Dec;33(1):397-404. doi: 10.1080/14756366.2017.1422125.
Shikimic acid (SA) pathway is the common route used by bacteria, plants, fungi, algae, and certain Apicomplexa parasites for the biosynthesis of aromatic amino acids and other secondary metabolites. As this essential pathway is absent in mammals designing inhibitors against implied enzymes may lead to the development of antimicrobial and herbicidal agents harmless to humans. Shikimate dehydrogenase (SDH) is the fourth enzyme of the SA pathway. In this contribution, a series of SA amide derivatives were synthesised and evaluated for in vitro SDH inhibition and antibacterial activity against Escherichia coli. All tested compounds showed to be mixed type inhibitors; diamide derivatives displayed more inhibitory activity than synthesised monoamides. Among the evaluated compounds, molecules called 4a and 4b were the most active derivatives with IC 588 and 589 µM, respectively. Molecular modelling studies suggested two different binding modes of monoamide and diamide derivatives to the SDH enzyme of E. coli.
莽草酸（SA）途径是细菌、植物、真菌、藻类和某些顶复门寄生虫用于生物合成芳香族氨基酸和其他次生代谢产物的常见途径。由于哺乳动物中不存在这种必需途径，设计针对相关酶的抑制剂可能会导致开发出对人类无害的抗菌和除草剂。莽草酸脱氢酶（SDH）是SA途径的第四个酶。在本研究中，合成了一系列SA酰胺衍生物，并评估了它们对SDH的体外抑制作用以及对大肠杆菌的抗菌活性。所有测试化合物均显示为混合型抑制剂；二酰胺衍生物比合成的单酰胺表现出更强的抑制活性。在评估的化合物中，名为4a和4b的分子是活性最高的衍生物，IC50分别为588和589 μM。分子模拟研究表明，单酰胺和二酰胺衍生物与大肠杆菌SDH酶有两种不同的结合模式。
