A Modular Synthetic Route Involving N-Aryl-2-nitrosoaniline Intermediates Leads to a New Series of 3-Substituted Halogenated Phenazine Antibacterial Agents.
A Modular Synthetic Route Involving N-Aryl-2-nitrosoaniline Intermediates Leads to a New Series of 3-Substituted Halogenated Phenazine Antibacterial Agents.
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DOI：
10.1021/acs.jmedchem.1c00168
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发表时间：
2021-06-10
影响因子：
7.3
通讯作者：
Huigens RW 3rd
中科院分区：
文献类型：
--
作者：
Yang H;Kundra S;Chojnacki M;Liu K;Fuse MA;Abouelhassan Y;Kallifidas D;Zhang P;Huang G;Jin S;Ding Y;Luesch H;Rohde KH;Dunman PM;Lemos JA;Huigens RW 3rd
病原菌表现出令人难以置信的能力，通过发展耐药性和形成休眠的表面附着的生物膜来逃避常规抗生素。因此，靶向和根除嗜酸性细菌和生物膜细菌的试剂具有重大意义。我们通过使用N-芳基-2-亚硝基苯胺合成中间体探索了一系列新的卤代吩嗪（HP），这些中间体能够使该支架的3位官能化。几种HP表现出有效的抗菌和生物膜杀伤活性（例如，HP 29，抗耐甲氧西林金黄色葡萄球菌：MIC = 0.075 μM; MBEC = 2.35 μM），转录分析显示HP 3、28和29诱导MRSA生物膜中的快速铁饥饿。几种HP对结核分枝杆菌表现出优异的活性（HP 34，对CDC 1551的MIC = 0.80 μM）。这项工作建立了新的SAR见解，HP 29在小鼠背部伤口感染模型中证明了疗效。受这些发现的鼓舞，我们相信HP可能会在治疗挑战性感染方面取得重大进展。
Pathogenic bacteria demonstrate incredible abilities to evade conventional antibiotics through the development of resistance and formation of dormant, surface-attached biofilms. Therefore, agents that target and eradicate planktonic and biofilm bacteria are of significant interest. We explored a new series of halogenated phenazines (HP) through the use of N-aryl-2-nitrosoaniline synthetic intermediates that enabled functionalization of the 3-position of this scaffold. Several HPs demonstrated potent antibacterial and biofilm-killing activities (e.g., HP 29, against methicillin-resistant Staphylococcus aureus: MIC = 0.075 μM; MBEC = 2.35 μM), and transcriptional analysis revealed that HPs 3, 28, and 29 induce rapid iron starvation in MRSA biofilms. Several HPs demonstrated excellent activities against Mycobacterium tuberculosis (HP 34, MIC = 0.80 μM against CDC1551). This work established new SAR insights, and HP 29 demonstrated efficacy in dorsal wound infection models in mice. Encouraged by these findings, we believe that HPs could lead to significant advances in the treatment of challenging infections.
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影响因子：
9.4
作者：
Ceri, H;Olson, ME;Buret, A
通讯作者：
Buret, A
影响因子：
4.9
作者：
Gupta, Rashmi;Felix, Carolina Rodrigues;Rohde, Kyle H.
通讯作者：
Rohde, Kyle H.
影响因子：
3.1
作者：
GILLASPY, AF;HICKMON, SG;SMELTZER, MS
通讯作者：
SMELTZER, MS
影响因子：
6.7
作者：
Colomer-Winter, Cristina;Flores-Mireles, Ana L.;Lemos, Jose A.
通讯作者：
Lemos, Jose A.
影响因子：
7.3
作者：
Abouelhassan, Yasmeen;Garrison, Aaron T.;Huigens, Robert W., III
通讯作者：
Huigens, Robert W., III