Ang M Trisha C, Gumbau-Brisa Roger, Allan David S, McDonald Robert, Ferguson Michael J, Holbein Bruce E, Bierenstiel Matthias
Chelation Partners Inc. , 1411 Oxford St. Suite 369 , Halifax , Nova Scotia B3H 3Z1 , Canada.
Department of Chemistry , Cape Breton University , 1250 Grand Lake Rd , Sydney , Nova Scotia B1P 6L2 , Canada . Email:
Medchemcomm. 2018 Jun 18;9(7):1206-1212. doi: 10.1039/c8md00192h. eCollection 2018 Jul 1.
Depriving microorganisms of bioavailable iron is a promising strategy for new anti-infective agents. The new, highly water-soluble, low molecular weight co-polymer DIBI was developed to selectively bind iron(iii) ions as a tris chelate and acts as a standalone anti-infective. Minimum inhibitory concentration (MIC) studies show DIBI is effective against representative reference strains for Gram-positive and Gram-negative bacteria and , and the fungus . Compared to the small molecule iron chelators, deferiprone and deferoxamine, DIBI outclassed these by factors of 100 to 1000 for inhibition of initial growth. DIBI and a series of related co-polymers ( of 2-9 kDa) were synthesized reversible addition-fragmentation chain transfer (RAFT) polymerization of a chelating 3-hydroxypyridin-4-one (HPO) methacrylamide monomer and -vinylpyrrolidone (NVP). Full incorporation of the HPO monomer into the co-polymers from the reaction solution was determined by H NMR spectroscopy and ranged from 4.6 to 25.6 mol%. UV-vis spectroscopy showed that all the HPO in DIBI binds readily to iron(iii) in a tris chelate mode to the maximum theoretical iron(iii) binding capacity of the co-polymer. Chemical characterization including single crystal X-ray diffraction analyses of the -benzyl protected and the functional HPO monomer are discussed. By design, DIBI is highly water soluble; the highest mass fraction in water tested was 70% w/w, without the need of organic co-solvents.
剥夺微生物可利用的铁是开发新型抗感染药物的一种有前景的策略。新型、高水溶性、低分子量共聚物DIBI被开发用于选择性地以三齿螯合物形式结合铁（III）离子，并作为一种独立的抗感染剂发挥作用。最低抑菌浓度（MIC）研究表明，DIBI对革兰氏阳性菌、革兰氏阴性菌以及真菌的代表性参考菌株均有效。与小分子铁螯合剂去铁酮和去铁胺相比，DIBI在抑制初始生长方面比它们高出100至1000倍。DIBI和一系列相关共聚物（2 - 9 kDa）是通过螯合3 - 羟基吡啶 - 4 - 酮（HPO）甲基丙烯酰胺单体和N - 乙烯基吡咯烷酮（NVP）的可逆加成 - 断裂链转移（RAFT）聚合反应合成的。通过1H NMR光谱法确定了HPO单体从反应溶液中完全掺入共聚物中，其范围为4.6至25.6摩尔％。紫外 - 可见光谱表明，DIBI中所有的HPO都以三齿螯合模式容易地与铁（III）结合，达到共聚物的最大理论铁（III）结合能力。讨论了包括苄基保护的和功能性HPO单体的单晶X射线衍射分析在内的化学表征。通过设计，DIBI具有高度水溶性；测试的水中最高质量分数为70％w / w，无需有机共溶剂。
