ABSTRACT
A series of dual-targeting, alcohol-containing benzothiazoles has been identified with superior antibacterial activity and drug-like properties. Early lead benzothiazoles containing carboxylic acid moieties showed efficacy in a well-established in vivo model, but inferior drug-like properties demanded modifications of functionality capable of demonstrating superior efficacy. Eliminating the acid group in favor of hydrophilic alcohol moieties at C(5), as well as incorporating solubilizing groups at the C(7) position of the core ring provided potent, broad-spectrum Gram-positive antibacterial activity, lower protein binding, and markedly improved efficacy in vivo.
Subject(s)
Anti-Bacterial Agents/pharmacology , Benzothiazoles/chemistry , Benzothiazoles/pharmacology , DNA, Bacterial/chemistry , DNA, Bacterial/drug effects , DNA, Superhelical/drug effects , Haemophilus influenzae/drug effects , Alcohols/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Benzothiazoles/chemical synthesis , Dose-Response Relationship, Drug , Drug Discovery , Microbial Sensitivity Tests , Molecular Structure , Staphylococcus , Structure-Activity RelationshipABSTRACT
The design, synthesis and structure-activity relationships of a series of oxazole-benzamide inhibitors of the essential bacterial cell division protein FtsZ are described. Compounds had potent anti-staphylococcal activity and inhibited the cytokinesis of the clinically-significant bacterial pathogen Staphylococcus aureus. Selected analogues possessing a 5-halo oxazole also inhibited a strain of S. aureus harbouring the glycine-to-alanine amino acid substitution at residue 196 of FtsZ which conferred resistance to previously reported inhibitors in the series. Substitutions to the pseudo-benzylic carbon of the scaffold improved the pharmacokinetic properties by increasing metabolic stability and provided a mechanism for creating pro-drugs. Combining multiple substitutions based on the findings reported in this study has provided small-molecule inhibitors of FtsZ with enhanced in vitro and in vivo antibacterial efficacy.
Subject(s)
Anti-Bacterial Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Benzamides/pharmacology , Cytoskeletal Proteins/antagonists & inhibitors , Drug Design , Oxazoles/pharmacology , Staphylococcus aureus/drug effects , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Benzamides/chemistry , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Molecular Structure , Oxazoles/chemistry , Staphylococcus aureus/chemistry , Structure-Activity RelationshipABSTRACT
The discovery and optimisation of a new class of benzothiazole small molecules that inhibit bacterial DNA gyrase and topoisomerase IV are described. Antibacterial properties have been demonstrated by activity against DNA gyrase ATPase and potent activity against Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes and Haemophilus influenzae. Further refinements to the scaffold designed to enhance drug-likeness included analogues bearing an α-substituent to the carboxylic acid group, resulting in excellent solubility and favourable pharmacokinetic properties.
Subject(s)
Benzothiazoles/chemistry , Benzothiazoles/pharmacology , DNA Topoisomerase IV/antagonists & inhibitors , Drug Design , Isonipecotic Acids/chemistry , Topoisomerase II Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/pharmacology , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Benzothiazoles/chemical synthesis , DNA Gyrase/chemistry , DNA Gyrase/metabolism , DNA Topoisomerase IV/metabolism , Enterococcus faecalis/drug effects , Enterococcus faecalis/enzymology , Enzyme Activation/drug effects , Haemophilus influenzae/drug effects , Haemophilus influenzae/enzymology , Half-Life , Mice , Microbial Sensitivity Tests , Rats , Staphylococcus aureus/drug effects , Staphylococcus aureus/enzymology , Streptococcus pyogenes/drug effects , Streptococcus pyogenes/enzymology , Topoisomerase II Inhibitors/chemistry , Topoisomerase II Inhibitors/pharmacokineticsABSTRACT
Vasopressin (AVP) is a hormone that stimulates an increase in water permeability through activation of V2 receptors in the kidney. The analogue of AVP, desmopressin, has proven an effective drug for diseases where a reduction of urine output is desired. However, its peptidic nature limits its bioavailability. We report herein the discovery of potent, nonpeptidic, benzylurea derived agonists of the vasopressin V2 receptor. We describe substitutions on the benzyl group to give improvements in potency and subsequent modifications to the urea end group to provide improvements in solubility and increased oral efficacy in a rat model of diuresis. The lead compound 20e (VA106483) is reported for the first time and has been selected for clinical development.
Subject(s)
Chemistry, Pharmaceutical/methods , Receptors, Vasopressin/agonists , Urea/chemistry , Administration, Oral , Animals , Caco-2 Cells , Diuresis , Dose-Response Relationship, Drug , Drug Design , Drug Evaluation, Preclinical , Humans , Models, Chemical , Rats , Rats, Brattleboro , SolubilityABSTRACT
A library of compounds targeted to the vasopressin/oxytocin family of receptors was screened for activity at a cloned human oxytocin receptor using a reporter gene assay. Potency and selectivity were optimised to afford compound 39, EC50 = 33 nM. This series of compounds represents the first disclosed, non-peptide, low molecular weight agonists of the hormone oxytocin (OT).
