Many
pathogens utilize the formation of pores in the membranes of target cells in
the process of infection. A majority of pore-forming proteins, both bacterial
and viral, are important virulence factors and are considered as valid targets
for the discovery of new drugs.
Earlier,
we developed a novel approach to inhibit their action [1], which is based on
the blocking of the target pore with molecules having the same symmetry as the
pore itself. Using β-cyclodextrin derivatives with seven-fold symmetry, we
identified inhibitors of several toxins produced by different bacteria such as B. anthracis, S. aureus, C. perfringens,
C. difficile and C. botulinum. As a result of these studies, we established a number
of lead compounds with promising protective properties, however, further
optimization is required.
Due
to the lack of high resolution X-ray structures, we performed a systematic
search of cyclodextrin-based structures which were similar to the lead
compounds. We have varied the electrostatic and lipophilic properties, as well
as the ionization and flexibility of the pendant groups.
Efficient
and feasible generalized procedures have been elaborated depending on the
targeted substituents. Simple (ar)alkylamino- or (ar)alkylthio derivatives were
prepared from perhalogeno cyclodextrins and (ar)alkylamines/thiolates.
Clickable reactants could be effectively prepared from perazido cyclodextrins
and triple bond containing reagents, while the amide bound substituents, like
amino acids or carboxylic acids, were prepared from the peramino cyclodextrins
and the corresponding carboxylic acids. Yields of these reactions were 50-100
%.
Optimized
synthesis of the regioselectively reactive (halogeno, azido, amino)
cyclodextrin key intermediates resulted in > 90 % yields in each step.
[1]
V. A. Karginov et. al.; Blocking anthrax lethal toxin at the protective antigen
channel by using structure-inspired drug design; PNAS 102(42) 15075–15080 (2005)
