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substituent of 7a is eclipsed with macrolactone ring. Since energy
difference between first ten conformations is only several kcal/mol
**
(3 kcal/mol at MMFF94x as well as at the B3LYP/6-31G level),
any of these conformations can be adopted depending on the entro-
pic and enthalpic effect within the active site.
In conclusion, it was shown here that urea and thiourea deriva-
tives of 3-decladinosyl-3-hydroxy azalides, although lacking a cladi-
nose sugar, showed noticeable antibacterial activity. The compound
6a was found to be significantly active against erythromycin-sus-
ceptible S. pneumoniae strain as well as efflux-mediated resistant
S. pneumoniae strain. Compound 6c showed the same antibacterial
activity as a control drug azithromycin against susceptible S. pneu-
moniae and S. pyogenes strains. Also some 3-decladinosyl-3-hydroxy
ureas6, 9, and thioureas 7, 10, maintain antibacterial activity against
Gram-negative pathogens H. influenzae and M. catarrhalis in compar-
ison to their parent 3-cladinosyl derivatives,32 and comparable to
azithromycin, but demonstrate a large improvement in comparison
with inactive 3-decladinosyl azithromycin 235 and other 3-decladi-
nosyl derivatives reported in the literature.27,29 The results pre-
sented here can be a further step in the development of new
decladinosyl azalides. Although the limited number of compounds
studied here can not allow for a comprehensive SAR analysis, they
can serve as a good platform to explore the nature of bacterial resis-
tance. Thus, this novel class of 3-decladinosyl-3-hydroxy azalides
represents the promising hit compounds, which can be a basis for
further modifications and development of novel potent antibacteri-
als, especially against efflux-mediated resistant S. pneumoniae.
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29. Bukvic´ Krajacic, M.; Novak, P.; Cindric, M.; Brajša, K.; Dumic, M.; Kujundzic, N.
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We are indebted to Ana Cikoš and Biserka Metelko for
Eur. J. Med. Chem. 2007, 52, 138.
performing NMR experiments. This work was supported by the
Croatian Ministry of Science, Education and Sports (Grant Nos.
119-1191342-1083 and 006-0000000-3216).
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