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.
How to stop disproportionation of a hydrochloride salt of a very weakly basic compound in a non-clinical suspension formulation
