Open AccessA Modular Synthetic Route Involving N-Aryl-2-nitrosoaniline Intermediates Leads to a New Series of 3-Substituted Halogenated Phenazine Antibacterial Agents
Author(s) -
Hongfen Yang,
Shivani Kundra,
Michaelle Chojnacki,
Ke Liu,
Marisa A. Fuse,
Yasmeen Abouelhassan,
Dimitris Kallifidas,
Peilan Zhang,
Guangtao Huang,
Shouguang Jin,
Yousong Ding,
Hendrik Luesch,
Kyle H. Rohde,
Paul M. Dunman,
José A. Lemos,
Robert W. Huigens
Publication year - 2021
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.1c00168
Subject(s) - biofilm , chemistry , bacteria , microbiology and biotechnology , staphylococcus aureus , aryl , mycobacterium tuberculosis , antibiotics , pathogenic bacteria , methicillin resistant staphylococcus aureus , antimicrobial , combinatorial chemistry , antibacterial activity , phenazine , biochemistry , tuberculosis , biology , organic chemistry , medicine , alkyl , genetics , pathology
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.