PMID- 25496770
OWN - NLM
STAT- MEDLINE
DCOM- 20150921
LR  - 20181119
IS  - 1464-3405 (Electronic)
IS  - 0960-894X (Linking)
VI  - 25
IP  - 2
DP  - 2015 Jan 15
TI  - Acinetobacter baumannii OxPhos inhibitors as selective anti-infective agents.
PG  - 378-83
LID - S0960-894X(14)01204-9 [pii]
LID - 10.1016/j.bmcl.2014.11.020 [doi]
AB  - The Gram-negative bacterium Acinetobacter baumannii is an opportunistic pathogen 
      in humans and infections are poorly treated by current therapy. Recent emergence 
      of multi-drug resistant strains and the lack of new antibiotics demand an 
      immediate action for development of new anti-Acinetobacter agents. To this end, 
      oxidative phosphorylation (OxPhos) was identified as a novel target for drug 
      discovery research. Consequently, a library of  approximately 10,000 compounds was screened 
      using a membrane-based ATP synthesis assay. One hit identified was the 
      2-iminobenzimidazole 1 that inhibited the OxPhos of A. baumannii with a modestly 
      high selectivity against mitochondrial OxPhos, and displayed an MIC of 25muM 
      (17mug/mL) against the pathogen. The 2-iminobenzimidazole 1 was found to inhibit 
      the type 1 NADH-quinone oxidoreductase (NDH-1) of A. baumannii OxPhos by a 
      biochemical approach. Among various derivatives that were synthesized to date, 
      des-hydroxy analog 5 is among the most active with a relatively tight SAR 
      requirement for the N'-aminoalkyl side chain. Analog 5 also showed less 
      cytotoxicity against NIH3T3 and HepG2 mammalian cell lines, demonstrating the 
      potential for this series of compounds as anti-Acinetobacter agents. Additional 
      SAR development and target validation is underway.
CI  - Copyright (c) 2014 Elsevier Ltd. All rights reserved.
FAU - Rubin, Harvey
AU  - Rubin H
AD  - University of Pennsylvania, 522 Johnson Pavilion, Philadelphia, PA 19104, United 
      States. Electronic address: rubinh@upenn.edu.
FAU - Selwood, Trevor
AU  - Selwood T
AD  - University of Pennsylvania, 522 Johnson Pavilion, Philadelphia, PA 19104, United 
      States.
FAU - Yano, Takahiro
AU  - Yano T
AD  - University of Pennsylvania, 522 Johnson Pavilion, Philadelphia, PA 19104, United 
      States.
FAU - Weaver, Damian G
AU  - Weaver DG
AD  - Fox Chase Chemical Diversity Center, Inc., 3805 Old Easton Rd., Doylestown, PA 
      18902, United States.
FAU - Loughran, H Marie
AU  - Loughran HM
AD  - Fox Chase Chemical Diversity Center, Inc., 3805 Old Easton Rd., Doylestown, PA 
      18902, United States.
FAU - Costanzo, Michael J
AU  - Costanzo MJ
AD  - Fox Chase Chemical Diversity Center, Inc., 3805 Old Easton Rd., Doylestown, PA 
      18902, United States.
FAU - Scott, Richard W
AU  - Scott RW
AD  - Fox Chase Chemical Diversity Center, Inc., 3805 Old Easton Rd., Doylestown, PA 
      18902, United States.
FAU - Wrobel, Jay E
AU  - Wrobel JE
AD  - Fox Chase Chemical Diversity Center, Inc., 3805 Old Easton Rd., Doylestown, PA 
      18902, United States.
FAU - Freeman, Katie B
AU  - Freeman KB
AD  - Fox Chase Chemical Diversity Center, Inc., 3805 Old Easton Rd., Doylestown, PA 
      18902, United States.
FAU - Reitz, Allen B
AU  - Reitz AB
AD  - Fox Chase Chemical Diversity Center, Inc., 3805 Old Easton Rd., Doylestown, PA 
      18902, United States. Electronic address: areitz@fc-cdci.com.
LA  - eng
GR  - R41 AI108196/AI/NIAID NIH HHS/United States
GR  - R41 AI 108196-01/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20141122
PL  - England
TA  - Bioorg Med Chem Lett
JT  - Bioorganic & medicinal chemistry letters
JID - 9107377
RN  - 0 (Anti-Bacterial Agents)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Benzimidazoles)
RN  - 0 (Small Molecule Libraries)
RN  - EC 1.6.5.11 (NADH dehydrogenase (quinone))
RN  - EC 1.6.99.- (Quinone Reductases)
SB  - IM
MH  - Acinetobacter Infections/*drug therapy/microbiology
MH  - Acinetobacter baumannii/*drug effects
MH  - Animals
MH  - Anti-Bacterial Agents/chemistry/*pharmacology
MH  - Antineoplastic Agents/chemistry/*pharmacology
MH  - Benzimidazoles/chemistry/*pharmacology
MH  - Cell Proliferation/*drug effects
MH  - Hep G2 Cells
MH  - Humans
MH  - Liver Neoplasms/drug therapy/pathology
MH  - Mice
MH  - Microbial Sensitivity Tests
MH  - Molecular Structure
MH  - NIH 3T3 Cells
MH  - Oxidative Phosphorylation/*drug effects
MH  - Quinone Reductases/metabolism
MH  - Small Molecule Libraries/chemistry/*pharmacology
MH  - Structure-Activity Relationship
OTO - NOTNLM
OT  - 2-Iminobenzimidazole
OT  - Acinetobacter baumannii
OT  - Anti-infective
OT  - Oxidative phosphorylation
EDAT- 2014/12/17 06:00
MHDA- 2015/09/22 06:00
CRDT- 2014/12/16 06:00
PHST- 2014/09/05 00:00 [received]
PHST- 2014/11/04 00:00 [revised]
PHST- 2014/11/06 00:00 [accepted]
PHST- 2014/12/16 06:00 [entrez]
PHST- 2014/12/17 06:00 [pubmed]
PHST- 2015/09/22 06:00 [medline]
AID - S0960-894X(14)01204-9 [pii]
AID - 10.1016/j.bmcl.2014.11.020 [doi]
PST - ppublish
SO  - Bioorg Med Chem Lett. 2015 Jan 15;25(2):378-83. doi: 10.1016/j.bmcl.2014.11.020. 
      Epub 2014 Nov 22.