Fragment-to-Hit-to-Lead Discovery of a Novel Pyridylurea Scaffold of ATP Competitive Dual Targeting Type II Topoisomerase Inhibiting Antibacterial Agents

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• 作者：Gregory S. Basarab ; John I. Manchester ; Shanta Bist ; P. Ann Boriack-Sjodin ; Brian Dangel ; Ruth Illingworth ; Brian A. Sherer ; Shubha Sriram ; Maria Uria-Nickelsen ; Ann E. Eakin
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：November 14, 2013
• 年：2013
• 卷：56
• 期：21
• 页码：8712-8735
• 全文大小：970K
• 年卷期：v.56,no.21(November 14, 2013)
• ISSN：1520-4804

文摘

The discovery and optimization of a new class of bacterial topoisomerase (DNA gyrase and topoisomerase IV) inhibitors binding in the ATP domain are described. A fragment molecule, 1-ethyl-3-(2-pyridyl)urea, provided sufficiently potent enzyme inhibition (32 渭M) to prompt further analogue work. Acids and acid isosteres were incorporated at the 5-pyridyl position of this fragment, bridging to a key asparagine residue, improving enzyme inhibition, and leading to measurable antibacterial activity. A CF₃-thiazole substituent at the 4-pyridyl position improved inhibitory potency due to a favorable lipophilic interaction. Promising antibacterial activity was seen versus the Gram-positive pathogens Staphylococcus aureus and Streptococcus pneumoniae and the Gram-negative pathogens Haemophilus influenzae and Moraxella catarrhalis. Precursor metabolite incorporation and mutant analysis studies support the mode-of-action, blockage of DNA synthesis by dual target topoisomerase inhibition. Compound 35 was efficacious in a mouse S. aureus disease model, where a 4.5-log reduction in colony forming units versus control was demonstrated.