spacer Crystal structure of a topoisomerase ATP inhibitor
Primary citation
Title Fragment-to-Hit-to-Lead Discovery of a Novel Pyridylurea Scaffold of ATP Competitive Dual Targeting Type II Topoisomerase Inhibiting Antibacterial Agents.
Authors Basarab, G.S.search; Manchester, J.I.search; Bist, S.search; Boriack-Sjodin, P.A.search; Dangel, B.search; Illingworth, R.search; Sherer, B.A.search; Sriram, S.search; Uria-Nickelsen, M.search; Eakin, A.E.search
Journal J.MED.CHEM.search vol:56, pag:8712-8735 (2013), Identifiers: PubMed ID (24098982)search DOI (10.1021/jm401208b)
Abstract The discovery and optimization of a new class of bacterial topoisomerase (DNA gyrase and topoisomerase IV) inhibitors binding in the ATP domain is described. A fragment molecule, 1-ethyl-3-(2-pyridyl)urea, provided sufficiently potent enzyme inhibition (32 M) to prompt further analog 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.
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