Rimpiläinen Tatu, Andrade Joana, Nunes Alexandra, Ntungwe Epole, Fernandes Ana S, Vale João R, Rodrigues João, Gomes João Paulo, Rijo Patricia, Candeias Nuno R
Laboratory of Chemistry and Bioengineering, Tampere University of Technology, Korkeakoulunkatu 8, 33101 Tampere, Finland.
CBIOS-Universidade Lusófona Research Center for Biosciences & Health Technologies, Campo Grande 376, 1749-024 Lisboa, Portugal.
ACS Omega. 2018 Nov 29;3(11):16191-16202. doi: 10.1021/acsomega.8b02381. eCollection 2018 Nov 30.
Multidrug-resistant bacteria are one of the current biggest threats to public health and are responsible for most nosocomial infections. Herein, we report the efficient and facile synthesis of antibacterial agents aminoalkylphenols, derived from 5-nitrosalicyladehyde and prepared through a Petasis borono-Mannich multicomponent reaction. Minimum inhibitory concentrations (MICs) as low as 1.23 μM for a chlorine derivative were determined for multidrug-resistant Gram-positive bacteria, namely, and , two of the main pathogens responsible for infections in a hospital environment. The most promising antibacterial agents were further tested against eight strains of four Gram-positive species in order to elucidate their antibacterial broadness. In vitro cytotoxicity assays of the most active aminoalkylphenol revealed considerably lower toxicity against mammalian cells, as concentrations one order of magnitude higher than the determined MICs were required to induce human keratinocyte cell death. The phenol moiety was verified to be important in deeming the antibacterial properties of the analyzed compounds, although no correlation between such properties and their antioxidant activity was observed. A density functional theory computational study substantiated the ability of aminoalkylphenols to serve as precursors of -quinone methides.
多重耐药菌是当前对公众健康的最大威胁之一，也是大多数医院感染的罪魁祸首。在此，我们报告了一种高效简便的抗菌剂氨基烷基酚的合成方法，该抗菌剂由5-亚硝基水杨醛衍生而来，并通过Petasis硼基-曼尼希多组分反应制备。对于多重耐药革兰氏阳性菌，即医院环境中引起感染的两种主要病原体金黄色葡萄球菌和粪肠球菌，测定了一种氯衍生物的最低抑菌浓度（MIC）低至1.23μM。为了阐明其抗菌广度，对最有前景的抗菌剂针对四种革兰氏阳性菌的八个菌株进行了进一步测试。最具活性的氨基烷基酚的体外细胞毒性试验表明，其对哺乳动物细胞的毒性相当低，因为诱导人角质形成细胞死亡需要比测定的MIC高一个数量级的浓度。尽管未观察到这些性质与其抗氧化活性之间的相关性，但已证实酚部分对于确定所分析化合物的抗菌性能很重要。密度泛函理论计算研究证实了氨基烷基酚作为醌甲基化物前体的能力。
