ABSTRACT
In 2013, the Centers for Disease Control highlighted Clostridium difficile as an urgent threat for antibiotic-resistant infections, in part due to the emergence of highly virulent fluoroquinolone-resistant strains. Limited therapeutic options currently exist, many of which result in disease relapse. We sought to identify molecules specifically targeting C. difficile in high-throughput screens of our diversity-oriented synthesis compound collection. We identified two scaffolds with apparently novel mechanisms of action that selectively target C. difficile while having little to no activity against other intestinal anaerobes; preliminary evidence suggests that compounds from one of these scaffolds target the glutamate racemase. In vivo efficacy data suggest that both compound series may provide lead optimization candidates.
Subject(s)
Amino Acid Isomerases/antagonists & inhibitors , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Clostridioides difficile/drug effects , Enterocolitis, Pseudomembranous/drug therapy , Heterocyclic Compounds, 2-Ring/pharmacology , Phenylurea Compounds/pharmacology , Pyrroles/pharmacology , Quinolines/pharmacology , Amino Acid Isomerases/genetics , Amino Acid Isomerases/metabolism , Animals , Anti-Bacterial Agents/chemical synthesis , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Clostridioides difficile/enzymology , Clostridioides difficile/genetics , Clostridioides difficile/growth & development , Drug Design , Enterocolitis, Pseudomembranous/microbiology , Enterocolitis, Pseudomembranous/mortality , Enterocolitis, Pseudomembranous/pathology , Female , Gene Expression , Gram-Negative Bacteria/drug effects , Gram-Negative Bacteria/growth & development , Gram-Positive Bacteria/drug effects , Gram-Positive Bacteria/growth & development , Heterocyclic Compounds, 2-Ring/chemical synthesis , Mice , Mice, Inbred C57BL , Microbial Sensitivity Tests , Phenylurea Compounds/chemical synthesis , Pyrroles/chemical synthesis , Quinolines/chemical synthesis , Species Specificity , Structure-Activity Relationship , Survival AnalysisABSTRACT
Comprehensive SAR studies were undertaken in the 3,4-diaminocyclobut-3-ene-1,2-dione class of CXCR2/CXCR1 receptor antagonists to explore the role of the heterocycle on chemokine receptor binding affinities, functional activity, as well as oral exposure in rat. The nature of the heterocycle as well as the requisite substitution pattern around the heterocycle was shown to have a dramatic effect on the overall biological profile of this class of compounds. The furyl class, particularly the 4-halo adducts, was found to possess superior binding affinities for both the CXCR2 and CXCR1 receptors, functional activity, as well as oral exposure in rat versus other heterocyclic derivatives.
Subject(s)
Cyclobutanes/chemistry , Cyclobutanes/pharmacology , Diamines/chemistry , Diamines/pharmacology , Receptors, Interleukin-8A/antagonists & inhibitors , Receptors, Interleukin-8B/antagonists & inhibitors , Animals , Cell Line , Cyclobutanes/chemical synthesis , Diamines/chemical synthesis , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Mice , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of 3,4- and 3,5-disubstituted phenyl-containing cyclobutenedione analogues were synthesized and evaluated as CXCR2 receptor antagonists. Variations in the disubstitution pattern of the phenyl ring afforded new compounds with potent CXCR2 binding affinity in the low nanomolar ranges. Moreover, two potent compounds 19 and 26 exhibited good oral pharmacokinetic profiles.
