Lóránd Tamás, Kocsis Béla, Sohár Pál, Nagy Gergely, József Pál, Kispál Gyula, László Renáta, Prókai László
Department of Human Biochemistry and Medical Chemistry, Faculty of Medicine, University Pécs, Szigeti út 12, H-7624 Pécs, Hungary.
Eur J Med Chem. 2002 Oct;37(10):803-12. doi: 10.1016/s0223-5234(02)01404-6.
New Mannich ketones of fused bicyclic ketones as 1-indanones and 1-tetralones were prepared using the classical acid-catalysed Mannich reaction. Known members of this family were used in comparative biological tests. Antibacterial activity of these new water-soluble compounds was reported against Pseudomonas aeruginosa, Escherichia coli, E. coli ReD31m4, Salmonella minnesota Re595, Shigella sonnei Re4350, Staphylococcus aureus, Staphylococcus saprophyticus, Micrococcus luteus and Bacillus subtilis standard strains. Human cytotoxicity of our new compounds was evaluated against HeLa cell line. Some compounds showed low cytotoxicity (56.738 nM mL(-1) for 24, 47.497 nM mL(-1) for 31 and 48.379 nM mL(-1) for 26) and proved to be efficient antibacterial agents against the Gram-positive and partly against E. coli strains. Minimum inhibitory concentrations (MIC) changed in the range of 1.56->200 microg mL(-1). The deep rough mutants showed (generally eight times) higher sensitivity toward the compounds than the smooth E. coli. Hence, the permeability of Gram-negative outer membrane can influence the MIC values of our compounds. A preliminary quantitative structure-activity relationship (QSAR) study indicated the maximum positive charge (MaxQ(+)) as the parameter that most significantly affected antibacterial activity against E. coli. In B. subtilis, the influence of a topological descriptor (first-order valence-connectivity index, XV1) was also revealed; however, other strains did not yield meaningful QSAR with the set of descriptors employed.
利用经典的酸催化曼尼希反应制备了作为1-茚酮和1-四氢萘酮的稠合双环酮的新型曼尼希酮。该家族的已知成员用于比较生物学测试。报道了这些新型水溶性化合物对铜绿假单胞菌、大肠杆菌、大肠杆菌ReD31m4、明尼苏达沙门氏菌Re595、宋内志贺氏菌Re4350、金黄色葡萄球菌、腐生葡萄球菌、藤黄微球菌和枯草芽孢杆菌标准菌株的抗菌活性。评估了我们新化合物对HeLa细胞系的人细胞毒性。一些化合物显示出低细胞毒性（24号化合物为56.738 nM mL(-1)，31号化合物为47.497 nM mL(-1)，26号化合物为48.379 nM mL(-1)），并被证明是针对革兰氏阳性菌和部分针对大肠杆菌菌株的有效抗菌剂。最低抑菌浓度（MIC）在1.56->200 μg mL(-1)范围内变化。深度粗糙突变体对这些化合物的敏感性（通常高八倍）高于光滑型大肠杆菌。因此，革兰氏阴性菌外膜的通透性会影响我们化合物的MIC值。初步的定量构效关系（QSAR）研究表明，最大正电荷（MaxQ(+)）是对抗大肠杆菌抗菌活性影响最显著的参数。在枯草芽孢杆菌中，还揭示了一个拓扑描述符（一阶价连接性指数，XV1）的影响；然而，其他菌株与所采用的描述符集未产生有意义的QSAR。
