Novel inhibitors of bacterial virulence: Development of 5,6-dihydrobenzo[h]quinazolin-4(3H)-ones for the inhibition of group A streptococcal streptokinase expression

• Published in: Bioorganic & medicinal chemistry Vol. 21; no. 7; pp. 1880 - 1897
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.04.2013; Elsevier
• Subjects: Animals; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - metabolism; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - toxicity; Antibiotic; Antibiotic resistance; Antivirulence; bacteria; Biochemistry & Molecular Biology; Biofilm; Biofilms - drug effects; Cell Survival - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Gene Expression Regulation, Bacterial - drug effects; Group A Streptococcus; HeLa Cells; human health; Humans; Life Sciences & Biomedicine; mechanism of action; Metabolic oxidation; Mice; Microsomes, Liver - metabolism; Pharmacology & Pharmacy; Physical Sciences; Quinazolines - chemistry; Quinazolines - metabolism; Quinazolines - pharmacology; Quinazolines - toxicity; Science & Technology; Solubility; Staphylococcus aureus; Streptococcal Infections - drug therapy; Streptococcal Infections - microbiology; Streptococcus; Streptococcus - drug effects; Streptococcus - enzymology; Streptococcus - genetics; Streptococcus - physiology; Streptokinase; Streptokinase - antagonists & inhibitors; Streptokinase - genetics; Streptokinase - metabolism; Structure-Activity Relationship; virulence; Virulence inhibitor; THY; SAR; HTS; VRE; MRM; EMS; MLM; Antivirulence; DMEM; Virulence inhibitor; Antibiotic; Streptokinase; Metabolic oxidation; MRSA; Antibiotic resistance; GAS; SK; Biofilm; Group A Streptococcus; ESI; CID; EPI; UNITED-STATES; MODEL; PLASMINOGEN; PSEUDOMONAS-AERUGINOSA; RESISTANCE; INFECTION; DERIVATIVES
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2013.01.046

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.