A Modular Synthetic Route Involving <i>N</i>-Aryl-2-nitrosoaniline Intermediates Leads to a New Series of 3-Substituted Halogenated Phenazine Antibacterial Agents.
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.
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 <i>N</i>-aryl-2-nitrosoaniline synthetic intermediates that enabled functionalization of the 3-position of this scaffold. Several HPs demonstrated potent antibacterial and biofilm-killing activities (<i>e.g.</i>, HP <b>29</b>, against methicillin-resistant <i>Staphylococcus aureus</i>: MIC = 0.075 μM; MBEC = 2.35 μM), and transcriptional analysis revealed that HPs <b>3</b>, <b>28</b>, and <b>29</b> induce rapid iron starvation in MRSA biofilms. Several HPs demonstrated excellent activities against <i>Mycobacterium tuberculosis</i> (HP <b>34</b>, MIC = 0.80 μM against CDC1551). This work established new SAR insights, and HP <b>29</b> 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.