Inhibitory Activity of Pyrroloisoxazolidine Derivatives against Chlamydia trachomatis.

The obligate intracellular bacterium Chlamydia trachomatis is a group of worldwide human pathogens that can lead to serious reproductive problems. The frequent clinical treatment failure promoted the development of novel antichlamydial agents. Here, we firstly reported a group of pyrroloisoxazolidine-inhibited C. trachomatis in a dose-dependent manner in vitro. Among them, compounds 1 and 2 exhibited the strongest inhibitory activity with IC50 values from 7.25 to 9.73 µM. The compounds disturbed the whole intracellular life cycle of C. trachomatis, mainly targeting the middle reticulate body proliferation stages. Besides, the compounds partially inhibited the chlamydial infection by reducing elementary body infectivity at high concentration. Our findings suggest the potential of pyrroloisoxazolidine derivatives as promising lead molecules for the development of antichlamydial agents.

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 activities. We found that a few of the synthesized 4-substituted phenazines could block the 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 the treatment of uninfected HeLa cells using WST-1 method. RESULTS: Most of the 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 further chemical modification on C-3 position rather than C-4 position of phenazine.