New insights into the binding mode of pyridine-3-carboxamide inhibitors of E. coli DNA gyrase.

Previously we have reported on a series of pyridine-3-carboxamide inhibitors of DNA gyrase and DNA topoisomerase IV that were designed using a computational de novo design approach and which showed promising antibacterial properties. Herein we describe the synthesis of additional examples from this series aimed specifically at DNA gyrase, along with crystal structures confirming the predicted mode of binding and in vitro ADME data which describe the drug-likeness of these compounds.

Applications of structure-based design to antibacterial drug discovery.

In recent years bacterial resistance has been observed against many of our current antibiotics, for instance most worryingly against the cephalosporins which are typically the last line of defence against many bacterial infections. Additionally the failure of high throughput screening in the discovery of new antibacterial drug leads has led to a decline in the number of antibacterial agents reaching the market. Alternative methods of drug discovery including structure based drug design are needed to meet the threats caused by the emergence of resistance. In this review we explore the latest advancements in the identification of new antibacterial agents through the use of a number of structure based drug design programs.

Refining the chemical toolbox to be fit for educational and practical purpose for drug discovery in the 21st Century.

We live in a time where exploration and generation of new knowledge is occurring on a colossal scale. Medicinal chemists have traditionally taken key roles in drug discovery; however, the many unmet medical demands in the healthcare sector emphasise the need to evolve the medicinal chemistry discipline. To rise to the challenges in the 21st Century there is a necessity to refine the chemical toolbox for educational and practical reasons. This review proposes modern strategies that are beneficial to teaching in academia but are also important reminders of strategies that can potentially lead to better drugs.

Computational methods to identify new antibacterial targets.

The development of resistance to all current antibiotics in the clinic means there is an urgent unmet need for novel antibacterial agents with new modes of action. One of the best ways of finding these is to identify new essential bacterial enzymes to target. The advent of a number of in silico tools has aided classical methods of discovering new antibacterial targets, and these programs are the subject of this review. Many of these tools apply a cheminformatic approach, utilizing the structural information of either ligand or protein, chemogenomic databases, and docking algorithms to identify putative antibacterial targets. Considering the wealth of potential drug targets identified from genomic research, these approaches are perfectly placed to mine this rich resource and complement drug discovery programs.

Pyridine-3-carboxamide-6-yl-ureas as novel inhibitors of bacterial DNA gyrase: structure based design, synthesis, SAR and antimicrobial activity.

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.