ABSTRACT
Synthetic studies of the antimicrobial secondary metabolite thiomuracin A (1) provided access to analogues in the Northern region (C2-C10). Selective hydrolysis of the C10 amide of lead compound 2 and subsequent derivatization led to novel carbon- and nitrogen-linked analogues (e.g., 3) which improved antibacterial potency across a panel of Gram-positive organisms. In addition, congeners with improved physicochemical properties were identified which proved efficacious in murine sepsis and hamster C. difficile models of disease. Optimal efficacy in the hamster model of C. difficile was achieved with compounds that possessed both potent antibacterial activity and high aqueous solubility.
Subject(s)
Anti-Bacterial Agents/pharmacology , Clostridioides difficile/drug effects , Clostridium Infections/drug therapy , Peptides, Cyclic/pharmacology , Thiazoles/pharmacology , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Cricetinae , Disease Models, Animal , Dose-Response Relationship, Drug , Mice , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Peptides, Cyclic/chemical synthesis , Peptides, Cyclic/chemistry , Solubility , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistryABSTRACT
Synthetic studies of the antimicrobial secondary metabolite thiomuracin A (1) were initiated to improve chemical stability and physicochemical properties. Functional group modifications of 1 included removing the C2-C7 side chain, derivatizing the C84 epoxide region, and altering the C44 hydroxyphenylalanine motif. The resulting derivatives simplified and stabilized the chemical structure and were evaluated for antibacterial activity relative to 1. The simplified structure and improved organic solubility of the derivatives facilitated isolation yields from fermentation broths and simplified the procedures involved for the process. These advancements increased material supply for continued medicinal chemistry optimization and culminated in the identification of 2, a structurally simplified and chemically stable analogue of 1 which retained potent antibiotic activity.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Peptides, Cyclic/chemical synthesis , Thiazoles/chemical synthesis , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Clostridioides difficile/drug effects , Crystallography, X-Ray , Enterococcus/drug effects , Escherichia coli/genetics , Escherichia coli/metabolism , Escherichia coli Proteins/biosynthesis , Escherichia coli Proteins/chemistry , Female , Gram-Positive Bacterial Infections/drug therapy , Male , Mice , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Peptide Elongation Factor Tu/chemistry , Peptides, Cyclic/chemistry , Peptides, Cyclic/pharmacology , Protein Synthesis Inhibitors/chemical synthesis , Protein Synthesis Inhibitors/chemistry , Protein Synthesis Inhibitors/pharmacology , Rats , Rats, Sprague-Dawley , Staphylococcus aureus/drug effects , Streptococcus pyogenes/drug effects , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacology , Transcription, Genetic/drug effectsABSTRACT
Clostridium difficile (C. difficile) is a Gram positive, anaerobic bacterium that infects the lumen of the large intestine and produces toxins. This results in a range of syndromes from mild diarrhea to severe toxic megacolon and death. Alarmingly, the prevalence and severity of C. difficile infection are increasing; thus, associated morbidity and mortality rates are rising. 4-Aminothiazolyl analogues of the antibiotic natural product GE2270 A (1) were designed, synthesized, and optimized for the treatment of C. difficile infection. The medicinal chemistry effort focused on enhancing aqueous solubility relative to that of the natural product and previous development candidates (2, 3) and improving antibacterial activity. Structure-activity relationships, cocrystallographic interactions, pharmacokinetics, and efficacy in animal models of infection were characterized. These studies identified a series of dicarboxylic acid derivatives, which enhanced solubility/efficacy profile by several orders of magnitude compared to previously studied compounds and led to the selection of LFF571 (4) as an investigational new drug for treating C. difficile infection.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Clostridioides difficile/drug effects , Enterocolitis, Pseudomembranous/drug therapy , Thiazoles/chemical synthesis , Animals , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Cricetinae , Crystallography, X-Ray , Enterococcus/drug effects , Escherichia coli Proteins/antagonists & inhibitors , Escherichia coli Proteins/chemistry , Female , Male , Mesocricetus , Mice , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Peptide Elongation Factor Tu/antagonists & inhibitors , Peptide Elongation Factor Tu/chemistry , Rats , Rats, Sprague-Dawley , Solubility , Staphylococcus aureus/drug effects , Streptococcus pyogenes/drug effects , Structure-Activity Relationship , Thiazoles/pharmacokinetics , WaterABSTRACT
4-Aminothiazolyl analogues of the antibiotic natural product GE2270 A (1) were designed, synthesized, and optimized for their activity against Gram positive bacterial infections. Optimization efforts focused on improving the physicochemical properties (e.g., aqueous solubility and chemical stability) of the 4-aminothiazolyl natural product template while improving the in vitro and in vivo antibacterial activity. Structure-activity relationships were defined, and the solubility and efficacy profiles were improved over those of previous analogues and 1. These studies identified novel, potent, soluble, and efficacious elongation factor-Tu inhibitors, which bear cycloalkylcarboxylic acid side chains, and culminated in the selection of development candidates amide 48 and urethane 58.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Carboxylic Acids/chemical synthesis , Gram-Positive Bacterial Infections/drug therapy , Peptides, Cyclic/chemical synthesis , Thiazoles/chemical synthesis , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Area Under Curve , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Crystallography, X-Ray , Drug Resistance, Bacterial , Female , Gram-Positive Bacteria/drug effects , Gram-Positive Bacteria/genetics , Male , Mice , Microbial Sensitivity Tests , Models, Molecular , Molecular Conformation , Mutation , Peptides, Cyclic/chemistry , Peptides, Cyclic/pharmacology , Rats , Rats, Sprague-Dawley , Sepsis/drug therapy , Solubility , Stereoisomerism , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacologyABSTRACT
Imidazole analogs of the antibiotic natural product GE2270 A (1) were designed, synthesized, and evaluated for gram positive bacteria growth inhibition. A recently reported, copper-mediated synthesis was exploited to prepare 4-thiazolyl imidazole analogs of 1. The synthesis described represents a structurally complex, natural product-based application of this recently reported synthetic methodology. In addition, the biological evaluation of the imidazole-based analogs further define the SAR of the 4-aminothiazolyl-based antibacterial template.
Subject(s)
Amines/chemical synthesis , Anti-Bacterial Agents , Gram-Positive Bacteria/drug effects , Imidazoles/chemistry , Peptides, Cyclic/chemistry , Thiazoles/chemical synthesis , Amines/chemistry , Amines/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Copper/chemistry , Escherichia coli/drug effects , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Microbial Sensitivity Tests , Molecular Structure , Peptides, Cyclic/pharmacology , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacologyABSTRACT
4-Aminothiazolyl analogues of the antibacterial natural product GE2270 A (1) were designed, synthesized, and evaluated for gram positive bacteria growth inhibition. The aminothiazole-based chemical template was evaluated for chemical stability, and its decomposition revealed a novel, structurally simplified, des-thiazole analogue of 1. Subsequent stabilization of the 4-aminothiazolyl functional motif was achieved and initial structure activity relationships defined.
