Elie Claude R, David Guillaume, Schmitzer Andreea R
Département de Chimie, Université de Montréal , CP 6128 Succursale Centre Ville, H3C 3J7, Montreal, Quebec, Canada.
J Med Chem. 2015 Mar 12;58(5):2358-66. doi: 10.1021/jm501979f. Epub 2015 Feb 25.
The development of low molecular weight anionophores is an emerging topic in chemistry, as the need for these compounds increases with the continuous discovery of pathologies involving anomalies in anion transport processes. Development of new concepts to initiate anion imbalance in living cells while fighting multidrug-resistant bacteria is a paramount topic. In this study, three series of compounds including N,N'-diphenylethynylbenzyl benzimidazolium salts (1 and 2), 1,1'-(pyridine-2,6-diyl)bis(3-(4-(phenylethynyl)benzyl)-1H-benzo[d]imidazol-3-ium) salts (3-5), and 1,1'-(pyridine-2,6-diylbis(methylene))bis(3-(4-(phenyl ethynyl)benzyl)-1H-benzo[d]imidazol-3-ium) salts (6-8) displaying high antimicrobial activity and low toxicity against human cells were designed, synthesized, and studied. The most potent compound displayed micromolar minimal inhibitory concentrations in different Gram-negative and Gram-positive bacteria, while its hemolytic activity remained around 10% or less, even after a prolonged period of exposure. The mechanism of action of these benzimidazolium salts on bacterial membrane was assessed by bioanalytical techniques including assays in model membrane liposomes, membrane depolarization studies, and scanning electron microscopy (SEM) in living bacteria.
随着涉及阴离子转运过程异常的病理学不断被发现，对这些化合物的需求增加，低分子量阴离子载体的开发成为化学领域一个新兴的课题。在对抗多重耐药细菌的同时，开发引发活细胞中阴离子失衡的新概念是一个至关重要的课题。在本研究中，设计、合成并研究了三类化合物，包括N,N'-二苯乙炔基苄基苯并咪唑盐（1和2）、1,1'-（吡啶-2,6-二基）双（3-（4-（苯乙炔基）苄基）-1H-苯并[d]咪唑-3-鎓）盐（3-5）以及1,1'-（吡啶-2,6-二基亚甲基）双（3-（4-（苯乙炔基）苄基）-1H-苯并[d]咪唑-3-鎓）盐（6-8），这些化合物对人类细胞显示出高抗菌活性和低毒性。最有效的化合物在不同的革兰氏阴性菌和革兰氏阳性菌中显示出微摩尔级的最低抑菌浓度，即使在长时间暴露后，其溶血活性仍保持在10%或更低。通过生物分析技术评估了这些苯并咪唑盐对细菌膜的作用机制，包括在模型膜脂质体中的测定、膜去极化研究以及对活细菌的扫描电子显微镜（SEM）观察。
