PMID- 23206863
OWN - NLM
STAT- MEDLINE
DCOM- 20130528
LR  - 20121218
IS  - 1464-3405 (Electronic)
IS  - 0960-894X (Linking)
VI  - 23
IP  - 1
DP  - 2013 Jan 1
TI  - Sulfonylpiperidines as novel, antibacterial inhibitors of Gram-positive 
      thymidylate kinase (TMK).
PG  - 169-73
LID - S0960-894X(12)01430-8 [pii]
LID - 10.1016/j.bmcl.2012.10.128 [doi]
AB  - 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.
CI  - Copyright (c) 2012 Elsevier Ltd. All rights reserved.
FAU - Martinez-Botella, Gabriel
AU  - Martinez-Botella G
AD  - AstraZeneca Infection Innovative Medicines, 35 Gatehouse Drive, Waltham, MA 
      02451, USA. gabriel@sagerx.com
FAU - Loch, James T
AU  - Loch JT
FAU - Green, Oluyinka M
AU  - Green OM
FAU - Kawatkar, Sameer P
AU  - Kawatkar SP
FAU - Olivier, Nelson B
AU  - Olivier NB
FAU - Boriack-Sjodin, P Ann
AU  - Boriack-Sjodin PA
FAU - Keating, Thomas A
AU  - Keating TA
LA  - eng
PT  - Journal Article
DEP - 20121105
PL  - England
TA  - Bioorg Med Chem Lett
JT  - Bioorganic & medicinal chemistry letters
JID - 9107377
RN  - 0 (Anti-Bacterial Agents)
RN  - 0 (Bacterial Proteins)
RN  - 0 (Piperidines)
RN  - 0 (Sulfonamides)
RN  - EC 2.7.4.4 (Nucleoside-Phosphate Kinase)
RN  - EC 2.7.4.9 (dTMP kinase)
SB  - IM
MH  - Anti-Bacterial Agents/chemical synthesis/*chemistry/pharmacology
MH  - Bacterial Proteins/*antagonists & inhibitors/metabolism
MH  - Binding Sites
MH  - Catalytic Domain
MH  - Crystallography, X-Ray
MH  - Gram-Positive Bacteria/drug effects
MH  - Microbial Sensitivity Tests
MH  - Molecular Docking Simulation
MH  - Nucleoside-Phosphate Kinase/*antagonists & inhibitors/metabolism
MH  - Piperidines/chemical synthesis/*chemistry/pharmacology
MH  - Staphylococcus aureus/*enzymology
MH  - Structure-Activity Relationship
MH  - Sulfonamides/chemical synthesis/*chemistry/pharmacology
EDAT- 2012/12/05 06:00
MHDA- 2013/05/29 06:00
CRDT- 2012/12/05 06:00
PHST- 2012/09/14 00:00 [received]
PHST- 2012/10/25 00:00 [revised]
PHST- 2012/10/29 00:00 [accepted]
PHST- 2012/12/05 06:00 [entrez]
PHST- 2012/12/05 06:00 [pubmed]
PHST- 2013/05/29 06:00 [medline]
AID - S0960-894X(12)01430-8 [pii]
AID - 10.1016/j.bmcl.2012.10.128 [doi]
PST - ppublish
SO  - Bioorg Med Chem Lett. 2013 Jan 1;23(1):169-73. doi: 10.1016/j.bmcl.2012.10.128. 
      Epub 2012 Nov 5.