ABSTRACT
The synthesis and antibacterial activity of a series of nocathiacin I derivatives (4-20) containing polar water solubilizing groups is described. Thiol-Michael adducts containing acidic polar groups have reduced antibacterial activity whereas those with basic polar groups have retained very good antibacterial activity.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Peptides/chemical synthesis , Sulfhydryl Compounds/chemical synthesis , Animals , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/pharmacology , Female , Intercellular Signaling Peptides and Proteins , Mice , Mice, Inbred ICR , Microbial Sensitivity Tests , Peptides/administration & dosage , Peptides/pharmacology , Staphylococcal Infections/drug therapy , Staphylococcus aureus/drug effects , Staphylococcus aureus/growth & development , Sulfhydryl Compounds/pharmacologyABSTRACT
Nocathiacin I (1) was converted to its deoxy indole analogue, nocathiacin II (2), another natural product, by a unique and facile chemical process. This process was applied to nocathiacin IV (4), generating the lactone analogue of glycothiohexide alpha (5), which was also prepared from nocathiacin II by a mild hydrolytic process. In contrast to glycothiohexide alpha (3), this lactone analogue (5) was found to exhibit in vivo antibacterial efficacy in an animal (mouse) infection model.
Subject(s)
Anti-Bacterial Agents/chemistry , Peptides, Cyclic/chemistry , Peptides/chemistry , Animals , Anti-Bacterial Agents/pharmacology , Disease Models, Animal , Intercellular Signaling Peptides and Proteins , Mice , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Peptides/pharmacology , Peptides, Cyclic/pharmacology , Thiazoles/chemistry , Thiazoles/pharmacologyABSTRACT
Several nocathiacin I analogues (4-35) were synthesized and evaluated for their antibacterial activity. Most of these semi-synthetic analogues retained very good in vitro and in vivo antibacterial activity of 1.
Subject(s)
Anti-Bacterial Agents , Peptides , Amines/chemical synthesis , Amines/chemistry , Amines/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Enterococcus faecalis/drug effects , Enterococcus faecalis/growth & development , Intercellular Signaling Peptides and Proteins , Microbial Sensitivity Tests , Molecular Structure , Peptides/chemical synthesis , Peptides/pharmacology , Staphylococcus aureus/drug effects , Staphylococcus aureus/growth & development , Streptococcus pneumoniae/drug effects , Streptococcus pneumoniae/growth & development , Structure-Activity RelationshipABSTRACT
The synthesis and antibacterial activity of a series of new nocathiacin I derivatives (1-12) containing polar water solubilizing groups is described. Most of these compounds exhibited potent antibacterial activity and have improved water solubility. In addition, compounds 5, 7-9 also exhibited potent in vivo activity.
