title: Discovery of Azaindole Ureas as a Novel Class of Bacterial Gyrase B Inhibitors.
abstract: The emergence and spread of multidrug resistant bacteria are widely believed to endanger human health. New drug targets and lead compounds exempt from cross-resistance with existing drugs are urgently needed. We report on the discovery of azaindole ureas as a novel class of bacterial gyrase B inhibitors and detail the story of their evolution from a de novo design hit based on structure-based drug design. These inhibitors show potent minimum inhibitory concentrations against fluoroquinolone resistant MRSA and other Gram-positive bacteria.
authors.affiliation: Cubist Pharmaceuticals Inc. , Lexington, Massachusetts 02421, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Cubist Pharmaceuticals Inc. , Lexington, Massachusetts 02421, United States.
authors.forename: Qingyi
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Cubist Pharmaceuticals Inc. , Lexington, Massachusetts 02421, United States.
authors.forename: Jason B
authors.initials: JB
authors.lastname: Cross
authors.affiliation: Cubist Pharmaceuticals Inc. , Lexington, Massachusetts 02421, United States.
authors.forename: Jan Antoinette C
authors.initials: JA
authors.lastname: Romero
authors.affiliation: Cubist Pharmaceuticals Inc. , Lexington, Massachusetts 02421, United States.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Poutsiaka
authors.affiliation: Cubist Pharmaceuticals Inc. , Lexington, Massachusetts 02421, United States.
authors.forename: Felix
authors.initials: F
authors.lastname: Epie
authors.affiliation: Cubist Pharmaceuticals Inc. , Lexington, Massachusetts 02421, United States.
authors.forename: Douglas
authors.initials: D
authors.lastname: Bevan
authors.affiliation: Cubist Pharmaceuticals Inc. , Lexington, Massachusetts 02421, United States.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Cubist Pharmaceuticals Inc. , Lexington, Massachusetts 02421, United States.
authors.forename: Yanzhi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Cubist Pharmaceuticals Inc. , Lexington, Massachusetts 02421, United States.
authors.forename: Ajit
authors.initials: A
authors.lastname: Chavan
authors.affiliation: Cubist Pharmaceuticals Inc. , Lexington, Massachusetts 02421, United States.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Cubist Pharmaceuticals Inc. , Lexington, Massachusetts 02421, United States.
authors.forename: Terence
authors.initials: T
authors.lastname: Moy
authors.affiliation: Cubist Pharmaceuticals Inc. , Lexington, Massachusetts 02421, United States.
authors.forename: Anu
authors.initials: A
authors.lastname: Daniel
authors.affiliation: Cubist Pharmaceuticals Inc. , Lexington, Massachusetts 02421, United States.
authors.forename: Kien
authors.initials: K
authors.lastname: Nguyen
authors.affiliation: Cubist Pharmaceuticals Inc. , Lexington, Massachusetts 02421, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: Chamberlain
authors.affiliation: Cubist Pharmaceuticals Inc. , Lexington, Massachusetts 02421, United States.
authors.forename: Nicole
authors.initials: N
authors.lastname: Carter
authors.affiliation: Cubist Pharmaceuticals Inc. , Lexington, Massachusetts 02421, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Shotwell
authors.affiliation: Cubist Pharmaceuticals Inc. , Lexington, Massachusetts 02421, United States.
authors.forename: Jared
authors.initials: J
authors.lastname: Silverman
authors.affiliation: Cubist Pharmaceuticals Inc. , Lexington, Massachusetts 02421, United States.
authors.forename: Chester A
authors.initials: CA
authors.lastname: Metcalf
authors.affiliation: Cubist Pharmaceuticals Inc. , Lexington, Massachusetts 02421, United States.
authors.forename: Dominic
authors.initials: D
authors.lastname: Ryan
authors.affiliation: Cubist Pharmaceuticals Inc. , Lexington, Massachusetts 02421, United States.
authors.forename: Blaise
authors.initials: B
authors.lastname: Lippa
authors.affiliation: Cubist Pharmaceuticals Inc. , Lexington, Massachusetts 02421, United States.
authors.forename: Roland E
authors.initials: RE
authors.lastname: Dolle
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018360:Crystallography, X-Ray; D027081:DNA Gyrase / Q000378:metabolism*; D006094:Gram-Positive Bacteria / Q000187:drug effects / Q000201:enzymology; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy / Q000382:microbiology; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology*; D008958:Models, Molecular; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology; D059005:Topoisomerase II Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology*
chemical_list: C522780:4-azaindole; D001426:Bacterial Proteins; D007211:Indoles; D059005:Topoisomerase II Inhibitors; D014508:Urea; D027081:DNA Gyrase