Your browser doesn't support javascript.
loading
Sulfonylpiperidines as novel, antibacterial inhibitors of Gram-positive thymidylate kinase (TMK).
Martínez-Botella, Gabriel; Loch, James T; Green, Oluyinka M; Kawatkar, Sameer P; Olivier, Nelson B; Boriack-Sjodin, P Ann; Keating, Thomas A.
Affiliation
  • Martínez-Botella G; AstraZeneca Infection Innovative Medicines, 35 Gatehouse Drive, Waltham, MA 02451, USA. gabriel@sagerx.com
Bioorg Med Chem Lett ; 23(1): 169-73, 2013 Jan 01.
Article in En | MEDLINE | ID: mdl-23206863
ABSTRACT
Thymidylate kinase (TMK) is an essential enzyme for DNA synthesis in bacteria, phosphorylating deoxythymidine monophosphate (dTMP) to deoxythymidine diphosphate (dTDP), and thus is a potential new antibacterial drug target. Previously, we have described the first potent and selective inhibitors of Gram-positive TMK, leading to in vivo validation of the target. Here, a structure-guided design approach based on the initial series led to the discovery of novel sulfonylpiperidine inhibitors of TMK. Formation of hydrogen bonds with Arg48 in Staphylococcus aureus TMK was key to obtaining excellent enzyme affinity, as verified by protein crystallography. Replacement of a methylene linker in the series by a sulfonamide was accomplished with retention of binding conformation. Further optimization of logD yielded phenol derivative 11, a potent inhibitor of TMK showing excellent MICs against a broad spectrum of Gram-positive bacteria and >10(5) selectivity versus the human TMK homologue.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Piperidines / Staphylococcus aureus / Sulfonamides / Bacterial Proteins / Nucleoside-Phosphate Kinase / Anti-Bacterial Agents Language: En Journal: Bioorg Med Chem Lett Journal subject: BIOQUIMICA / QUIMICA Year: 2013 Document type: Article Affiliation country: Estados Unidos

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Piperidines / Staphylococcus aureus / Sulfonamides / Bacterial Proteins / Nucleoside-Phosphate Kinase / Anti-Bacterial Agents Language: En Journal: Bioorg Med Chem Lett Journal subject: BIOQUIMICA / QUIMICA Year: 2013 Document type: Article Affiliation country: Estados Unidos