Novel inhibitors of bacterial virulence: Development of 5,6-dihydrobenzo[h]quinazolin-4(3H)-ones for the inhibition of group A streptococcal streptokinase expression
Resistance to antibiotics is an increasingly dire threat to human health that warrants the development of new modes of treating infection. We recently identified 1 (CCG-2979) as an inhibitor of the expression of streptokinase, a critical virulence factor in Group A Streptococcus that endows blood-borne bacteria with fibrinolytic capabilities. In this report, we describe the synthesis and biological evaluation of a series of novel 5,6-dihydrobenzo[h] quinazolin-4(3H)-one analogs of 1 undertaken with the goal of improving the modest potency of the lead. In addition to achieving an over 35-fold increase in potency, we identified structural modifications that improve the solubility and metabolic stability of the scaffold. The efficacy of two new compounds 12c (CCG-203592) and 12k (CCG-205363) against biofilm formation in Staphylococcus aureus represents a promising additional mode of action for this novel class of compounds.
Yestrepsky, Bryan D.,Xu, Yuanxi,Breen, Meghan E.,Li, Xiaoqin,Rajeswaran, Walajapet G.,Ryu, Jenny G.,Sorenson, Roderick J.,Tsume, Yasuhiro,Wilson, Michael W.,Zhang, Wenpeng,Sun, Duxin,Sun, Hongmin,Larsen, Scott D.
p. 1880 - 1897
(2013/05/08)
1,3-Dihydro-3-(2-hydroxy-, 2-bromo- or 2-chloroethyl)-2H-isoindol-1-one derivatives
Derivatives of 1,3-dihydro-3-(2-hydroxyethyl) -2H-isoindol-1-one are disclosed. The derivatives are useful for treating ulcers in a mammal and for preventing or decreasing the secretion or availability of excessive amounts of gastric or hydrochloric acid in a mammal suffering from hyperchlorhydria and/or associated conditions.
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(2008/06/13)
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