Synthesis and Assessment of Novel Anti-chlamydial Benzylidene Acylhydrazides Derivatives

Abstract

Background: Chlamydiae, characterized by a unique biphasic life cycle, are a group of Gram-negative obligate intracellular bacterial pathogens responsible for diseases in a range of hosts including humans. Benzylidene acylhydrazide CF0001 could inhibit chlamydiae independent of iron starvation and T3SS inhibition. This finding promoted us to design and synthesize more benzylidene acylhydrazides to find novel anti-chlamydial agents. Methods: The carboxylic acids 1a-1d were coupled with Boc-hydrazide inpresence of EDCI and DMAP to obtain the intermediate 2a-2d in 60-62% yields. N-Boc deprotections were performed to obtain hydrazide hydrochloride salt 3a-3d. Nextly, the hydrazides were subjected to condensation with aldehydes to obtain benzylidene acylhydrazides 4a-4g in 30-52% yields in two steps. Results: Compound 4d exhibited best inhibitory effect on the formation and growth of chlamydial inclusions. The IC50 value of compound 4d for infectious progenies was 3.55 µM, better than 7.30 µM of CF0001. Conclusion: To find novel anti-chlamydial agents, we have designed and synthesized benzylidene acylhydrazides 4a-4g. Compounds 4a, 4d, 4g showed inhibitory activity on C. muridarum with the IC50 values from 3.55-12 µM. The 3,5-dibromo-4-hydroxyl substitutes on ring B are critical to keep their anti-chlamydial activity. Compound 4d inhibited C. muridarum in a dose-dependent manner without apparent cytotoxicity.

Pyocyanin Inhibits Chlamydia Infection by Disabling Infectivity of the Elementary Body and Disrupting Intracellular Growth

“…Although they are susceptible to several broad-spectrum antibiotics, clinical treatment failure is not uncommon. Without effective vaccines, there have been serious and continuous efforts to discover and develop new antichlamydials (4,(22)(23)(24)(25)(26)(27), particularly selective antichlamydials lacking adverse effects on the microbiota (4,22,23). In a search for natural compounds with antichlamydial activities, we identified pyocyanin as an antichlamydial with an IC 50 that is comparable to the IC 50 of tetracycline ( Fig.…”

“…Pooled sera collected from BALB/c mice intranasally inoculated with C. pneumoniae AR39 EBs were used to stain inclusions and EBs of this organism. A mouse polyclonal anti-MoPn antibody generated in the same manner by our lab was used for C. muridarum MoPn detection (23).…”

“…Although extensive efforts have been devoted to vaccine development during the past few decades, no vaccine effective against human chlamydial diseases has been developed to date (20,21). These facts necessitate identification of novel antichlamydials through chemical synthesis (4,(22)(23)(24) and/or from natural sources (25)(26)(27).…”