ABSTRACT
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.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Quinazolines/chemistry , Quinazolines/pharmacology , Streptococcus/enzymology , Streptokinase/antagonists & inhibitors , Animals , Anti-Bacterial Agents/metabolism , Anti-Bacterial Agents/toxicity , Biofilms/drug effects , Cell Survival/drug effects , Gene Expression Regulation, Bacterial/drug effects , HeLa Cells , Humans , Mice , Microsomes, Liver/metabolism , Quinazolines/metabolism , Quinazolines/toxicity , Solubility , Streptococcal Infections/drug therapy , Streptococcal Infections/microbiology , Streptococcus/drug effects , Streptococcus/genetics , Streptococcus/physiology , Streptokinase/genetics , Streptokinase/metabolism , Structure-Activity RelationshipABSTRACT
We recently identified bis(amide) CCG-1423 (1) as a novel inhibitor of RhoA/C-mediated gene transcription that is capable of inhibiting invasion of PC-3 prostate cancer cells in a Matrigel model of metastasis. An initial structure-activity relationship study focusing on bioisosteric replacement of the amides and conformational restriction identified two compounds, 4g and 8, with improved selectivity for inhibition of RhoA/C-mediated gene transcription and attenuated cytotoxicity relative to 1. Both compounds were also capable of inhibiting cell invasion with equal efficacy to 1 but with less attendant cytotoxicity.