Bakka Thomas A, Strøm Morten B, Andersen Jeanette H, Gautun Odd R
Department of Chemistry, Norwegian University of Science and Technology (NTNU), NO-7491 Trondheim, Norway.
Department of Pharmacy, Faculty of Health Sciences, UiT - The Arctic University of Norway, NO-9037 Tromsø, Norway.
Bioorg Med Chem. 2017 Oct 15;25(20):5380-5395. doi: 10.1016/j.bmc.2017.07.060. Epub 2017 Jul 29.
A library of 29 small 1,4-substituted 1,2,3-triazoles was prepared for studies of antimicrobial activity. The pharmacophore model investigated with these substrates was based on small peptidomimetics of antimicrobial peptides and antimicrobials isolated from marine organisms from sub-arctic regions. Using methyl 1,2,3-triazole-carboxylates and 1,2,3-triazole methyl ketones prepared through "click" chemistry we were able to synthesize the different cationic amphiphiles through three steps or less. Several structural modifications to the lipopohilic side and hydrophilic sides of the amphiphiles were investigated and compared with regards to antimicrobial activity and cytotoxicity in particular. The most promising amphiphile 10f displayed minimum inhibitory concentrations (MICs) between 4-16µg/mL against Gram-positive Enterococcus faecalis, Staphylococcus aureus, Streptococcus agalacticae, and Gram-negative Escherichia coli and Pseudomonas aeruginosa. The decent level of antimicrobial activity and biofilm inhibition, short synthesis, and accessible reagents, makes this type of amphiphilic mimics interesting leads for further development.
制备了一个包含29种1,4-取代的1,2,3-三唑小分子的文库，用于抗菌活性研究。用这些底物研究的药效团模型基于抗菌肽的小分子拟肽以及从亚北极地区海洋生物中分离出的抗菌剂。通过“点击”化学制备的1,2,3-三唑羧酸甲酯和1,2,3-三唑甲基酮，我们能够通过三步或更少步骤合成不同的阳离子两亲物。研究了两亲物亲脂侧和亲水侧的几种结构修饰，并特别比较了它们的抗菌活性和细胞毒性。最有前景的两亲物10f对革兰氏阳性粪肠球菌、金黄色葡萄球菌、无乳链球菌以及革兰氏阴性大肠杆菌和铜绿假单胞菌的最低抑菌浓度（MIC）在4-16μg/mL之间。这种两亲物模拟物具有良好的抗菌活性和生物膜抑制能力、合成步骤短以及试剂易得等特点，使其成为进一步开发的有趣先导物。
