ABSTRACT
INTRODUCTION: There is a growing need for new antibacterial agents, but success in development of antibiotics in recent years has been limited. This has led researchers to investigate novel approaches to finding compounds that are effective against multi-drug resistant bacteria, and that delay onset of resistance. One such strategy has been to link antibiotics to produce hybrids designed to overcome resistance mechanisms. AREAS COVERED: The concept of dual-acting hybrid antibiotics was introduced and reviewed in this journal in 2010. In the present review the authors sought to discover how clinical candidates described had progressed, and to examine how the field has developed. In three sections the authors cover the clinical progress of hybrid antibiotics, novel agents produced from hybridisation of two or more small-molecule antibiotics, and novel agents produced from hybridisation of antibiotics with small-molecules that have complementary activity. EXPERT OPINION: Many key questions regarding dual-acting hybrid antibiotics remain to be answered, and the proposed benefits of this approach are yet to be demonstrated. While Cadazolid in particular continues to progress in the clinic, suggesting that there is promise in hybridisation through covalent linkage, it may be that properties other than antibacterial activity are key when choosing a partner molecule.
Subject(s)
Anti-Bacterial Agents/pharmacology , Bacterial Infections/drug therapy , Drug Design , Animals , Anti-Bacterial Agents/chemistry , Bacterial Infections/microbiology , Drug Resistance, Multiple, Bacterial , Humans , Oxazolidinones/chemistry , Oxazolidinones/pharmacologyABSTRACT
The development of antibacterial drugs based on novel chemotypes is essential to the future management of serious drug resistant infections. We herein report the design, synthesis and SAR of a novel series of N-ethylurea inhibitors based on a pyridine-3-carboxamide scaffold targeting the ATPase sub-unit of DNA gyrase. Consideration of structural aspects of the GyrB ATPase site has aided the development of this series resulting in derivatives that demonstrate excellent enzyme inhibitory activity coupled to potent Gram positive antibacterial efficacy.
Subject(s)
Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , DNA Gyrase/metabolism , Drug Design , Topoisomerase II Inhibitors/pharmacology , Urea/analogs & derivatives , Urea/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Bacteria/enzymology , Bacteria/metabolism , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Topoisomerase II Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/chemistry , Urea/chemical synthesis , Urea/chemistryABSTRACT
We herein report the discovery of a novel class of antagonists of the human adenosine A2B receptor. This low molecular weight scaffold has been optimized to offer derivatives with potential utility for the alleviation of conditions associated with this receptor subtype, such as nociception, diabetes, asthma and COPD. Furthermore, preliminary pharmacokinetic analysis has revealed compounds with profiles suitable for either inhaled or systemic routes of administration.
Subject(s)
Adenosine A2 Receptor Antagonists , Pyrimidines/chemistry , Administration, Inhalation , Animals , Asthma/drug therapy , Drug Design , Humans , Pulmonary Disease, Chronic Obstructive/drug therapy , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Rats , Receptor, Adenosine A2A/metabolism , Receptor, Adenosine A2B/metabolismABSTRACT
Antagonists of the human A(2A) receptor have been reported to have potential therapeutic benefit in the alleviation of the symptoms associated with neurodegenerative movement disorders such as Parkinson's disease. As part of our efforts to discover potent and selective antagonists of this receptor, we herein describe the detailed optimization and structure-activity relationships of a series of pyrimidine-4-carboxamides. These optimized derivatives display desirable physiochemical and pharmacokinetic profiles, which have led to promising oral activity in clinically relevant models of Parkinson's disease.
