Synthesis and Assessment of 3-Substituted Phenazines as Novel Antichlamydial Agents

BACKGROUND: In the past century, many phenazines were isolated from the marine microorganism, and some of these phenazines possessed potent antibacterial activites. We found that a few of the synthesized 4-substituted phenazines could block infectivity of chlamydiae without host cell toxicity. OBJECTIVE: The aim of this study was to design and synthesize two series of novel 3-substituted phenazines to find novel antichlamydial agents. METHODS: The 3-substituted phenazines were synthesized via Buchwald-Hartwig cross coupling reaction and Suzuki reaction from 3-bromo-1-methoxyphenazine. The antichlamydial activity of these synthesized compounds was evaluated by determining their effect on the yield of infectious progeny EBs. Cytotoxicity of these compounds on host cells was assessed by treatment of uninfected HeLa cells using WST-1 method. RESULTS: Most of 3-substituted phenazines possessed potent antichlamydial activity with IC50 values from 0.15 to 12.08 μM against Chlamydia trachomatis L2, C. muridarum MoPn and C. pneumoniae AR39. Among them, 7d and 9a exhibited better antichlamydial activity with IC50 values from 0.20 to 1.01 μM while they have no apparent cytotoxicity to host cells. Biological assay disclosed that both 7d and 9a inhibited chlamydial infection by reducing elementary body infectivity and disturbing chlamydial growth during the whole chlamydial developmental cycle. CONCLUSION: Our findings suggested that 3-substituted phenazine derivatives might be a promising class of therapeutic agents for chlamydial infections. More effective phenazines with low toxicity could be acquired through futher chemical modification on C-3 position rather than C-4 position of phenazine.