Relevant articles and documents
An Efficient Buchwald-Hartwig/Reductive Cyclization for the Scaffold Diversification of Halogenated Phenazines: Potent Antibacterial Targeting, Biofilm Eradication, and Prodrug Exploration
Garrison, Aaron T. Abouelhassan, Yasmeen Kallifidas, Dimitris Tan, Hao Kim, Young S. Jin, Shouguang Luesch, Hendrik Huigens, Robert W.
Bacterial biofilms are surface-attached communities comprised of nonreplicating persister cells housed within a protective extracellular matrix. Biofilms display tolerance toward conventional antibiotics, occur in ～80% of infections, and lead to >500000 deaths annually. We recently identified halogenated phenazine (HP) analogues which demonstrate biofilm-eradicating activities against priority pathogens; however, the synthesis of phenazines presents limitations. Herein, we report a refined HP synthesis which expedited the identification of improved biofilm-eradicating agents. 1-Methoxyphenazine scaffolds were generated through a Buchwald-Hartwig cross-coupling (70% average yield) and subsequent reductive cyclization (68% average yield), expediting the discovery of potent biofilm-eradicating HPs (e.g., 61: MRSA BAA-1707 MBEC = 4.69 μM). We also developed bacterial-selective prodrugs (reductively activated quinone-alkyloxycarbonyloxymethyl moiety) to afford HP 87, which demonstrated excellent antibacterial and biofilm eradication activities against MRSA BAA-1707 (MIC = 0.15 μM, MBEC = 12.5 μM). Furthermore, active HPs herein exhibit negligible cytotoxic or hemolytic effects, highlighting their potential to target biofilms.
Synthesis and antichlamydial activity of novel phenazines
Bao, Xiaofeng Yu, Xiaowei Xia, Chao Yang, Ningjing Yang, Shengju Zhao, Yu
Background: Chlamydiae are widespread Gram-negative bacteria that cause a number of human diseases. Chlamydia trachomatis is the most prevalent sexually transmitted bacterial pathogen. Methods: Fourteen novel phenazine derivatives were efficiently synthesized via Buchwald-Hartwig cross coupling reaction and Suzuki reaction from 4-bromo-1-methoxyphenazine. All the derivatives displayed antichlamydial activity with IC50 values from 1.01-19.77 μM against Chlamydia trachomatis D and L2 for inhibiting progeny formation. Results: C-4 morpholinyl 8a and C-4 phenyl phenazine 9c exhibited stronger antichlamydial activity with no apparent cytotoxicity. Both phenazine derivatives inhibited chlamydial inclusions formation and growth in a dose-dependent manner. They inhibited Chlamydia infection by reducing elementary body infectivity and disturbing Chlamydia growth at the mid-stage of the chlamydial developmental cycle. Conclusion: Our findings suggest C-4 aryl and C-4 amino phenazine derivatives as promising lead molecules for antichlamydials development.
Germany | Contact:Sir
United Kingdom | Contact:Elsa Young
China (Mainland) | Contact:Linna