Subject(s)
Adenine/analogs & derivatives , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Pyrazoles/chemistry , Adenine/chemical synthesis , Adenine/chemistry , Adenine/pharmacology , Binding Sites , Computer Simulation , Drug Evaluation, Preclinical , HSP90 Heat-Shock Proteins/metabolism , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , ThermodynamicsABSTRACT
Heat shock protein 90 (Hsp90) plays a key role in stress response and protection of the cell against the effects of mutation. Herein we report the identification of an Hsp90 inhibitor identified by fragment screening using a high-concentration biochemical assay, as well as its optimisation by in silico searching coupled with a structure-based drug design (SBDD) approach.
Subject(s)
HSP90 Heat-Shock Proteins/antagonists & inhibitors , Oximes/chemistry , Pyrimidines/chemistry , Binding Sites , Cell Line, Tumor , Computer Simulation , Crystallography, X-Ray , Drug Design , HSP90 Heat-Shock Proteins/metabolism , Humans , Oximes/chemical synthesis , Oximes/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Structure-Activity RelationshipABSTRACT
The synthesis and antibacterial activities of three chemotypes of DNA supercoiling inhibitors based on imidazolo[1,2-a]pyridine and [1,2,4]triazolo[1,5-a]pyridine scaffolds that target the ATPase subunits of DNA gyrase and topoisomerase IV (GyrB/ParE) is reported. The most potent scaffold was selected for optimization leading to a series with potent Gram-positive antibacterial activity and a low resistance frequency.
Subject(s)
Anti-Infective Agents/pharmacology , Chemistry, Pharmaceutical/methods , DNA Topoisomerase IV/antagonists & inhibitors , Topoisomerase II Inhibitors , Adenosine Triphosphatases/antagonists & inhibitors , Adenosine Triphosphatases/chemistry , Drug Design , Enterococcus faecalis/metabolism , Escherichia coli/metabolism , Gram-Positive Bacteria/metabolism , Humans , Imidazoles/chemistry , Inhibitory Concentration 50 , Pyridines/chemistry , Staphylococcus aureus/metabolism , Structure-Activity Relationship , Triazoles/chemistryABSTRACT
3-Methoxybenzamide is a weak inhibitor of the essential bacterial cell division protein FtsZ. Exploration of the structure-activity relationships of 3-methoxybenzamide analogues led to the identification of potent anti-staphylococcal compounds.
