Thorsteinsson Thorsteinn, Másson Már, Kristinsson Karl G, Hjálmarsdóttir Martha A, Hilmarsson Hilmar, Loftsson Thorsteinn
Faculty of Pharmacy, University of Iceland, Hagi, Hofsvallagata 53, IS-107 Reykjavik, Iceland.
J Med Chem. 2003 Sep 11;46(19):4173-81. doi: 10.1021/jm030829z.
A series of soft quaternary ammonium antimicrobial agents, which are analogues to currently used quaternary ammonium preservatives such as cetyl pyridinium chloride and benzalkonium chloride, were synthesized. These soft analogues consist of long alkyl chain connected to a polar headgroup via chemically labile spacer group. They are characterized by facile nonenzymatic and enzymatic degradation to form their original nontoxic building blocks. However, their chemical stability has to be adequate in order for them to have antimicrobial effects. Stability studies and antibacterial and antiviral activity measurements revealed relationship between activity, lipophilicity, and stability. Their minimum inhibitory concentration (MIC) was as low as 1 microg/mL, and their viral reduction was in some cases greater than 6.7 log. The structure-activity studies demonstrate that the bioactive compounds (i.e., MIC for Gram-positive bacteria of <10 microg/mL) have an alkyl chain length between 12 and 18 carbon atoms, with a polar headgroup preferably of a small quaternary ammonium group, and their acquired inactivation half-life must be greater than 3 h at 60 degrees C.
合成了一系列软质季铵抗菌剂，它们是当前使用的季铵防腐剂（如十六烷基氯化吡啶和苯扎氯铵）的类似物。这些软质类似物由通过化学不稳定间隔基团连接到极性头基的长烷基链组成。它们的特点是易于通过非酶和酶降解形成其原始无毒的组成部分。然而，它们的化学稳定性必须足够，以便具有抗菌作用。稳定性研究以及抗菌和抗病毒活性测量揭示了活性、亲脂性和稳定性之间的关系。它们的最低抑菌浓度（MIC）低至1微克/毫升，在某些情况下，它们的病毒减少率大于6.7对数。构效关系研究表明，生物活性化合物（即对革兰氏阳性菌的MIC<10微克/毫升）的烷基链长度在12至18个碳原子之间，极性头基最好是小的季铵基团，并且它们在60℃下获得的失活半衰期必须大于3小时。
