title: Novel inhibitors of bacterial virulence: development of 5,6-dihydrobenzo[h]quinazolin-4(3H)-ones for the inhibition of group A streptococcal streptokinase expression.
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.
authors: Vahlteich Medicinal Chemistry Core, Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, United States.
authors: Bryan D
authors: BD
authors: Yestrepsky
authors: Yuanxi
authors: Y
authors: Xu
authors: Meghan E
authors: ME
authors: Breen
authors: Xiaoqin
authors: X
authors: Li
authors: Walajapet G
authors: WG
authors: Rajeswaran
authors: Jenny G
authors: JG
authors: Ryu
authors: Roderick J
authors: RJ
authors: Sorenson
authors: Yasuhiro
authors: Y
authors: Tsume
authors: Michael W
authors: MW
authors: Wilson
authors: Wenpeng
authors: W
authors: Zhang
authors: Duxin
authors: D
authors: Sun
authors: Hongmin
authors: H
authors: Sun
authors: Scott D
authors: SD
authors: Larsen
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D018441:Biofilms / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D011799:Quinazolines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D012995:Solubility; D013290:Streptococcal Infections / Q000188:drug therapy / Q000382:microbiology; D013291:Streptococcus / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics / Q000502:physiology; D013300:Streptokinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; C571730:CCG-2979; D011799:Quinazolines; D013300:Streptokinase