title: Structure-based design, synthesis, and antimicrobial activity of indazole-derived SAH/MTA nucleosidase inhibitors.
abstract: The structure-based design, synthesis, and biological activity of a novel indazole-containing inhibitor series for S-adenosyl homocysteine/methylthioadenosine (SAH/MTA) nucleosidase are described. Use of 5-aminoindazole as the core scaffold provided a structure-guided series of low nanomolar inhibitors with broad-spectrum antimicrobial activity. The implementation of structure-based methodologies provided a 6000-fold increase in potency over a short timeline (several months) and an economy of synthesized compounds.
authors.affiliation: Department of Medicinal Chemistry, Quorex Pharmaceuticals, 1890 Rutherford Drive, Carlsbad, CA 92008, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Li
authors.forename: Sam
authors.initials: S
authors.lastname: Chu
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Feher
authors.forename: Mitra
authors.initials: M
authors.lastname: Khalili
authors.forename: Zhe
authors.initials: Z
authors.lastname: Nie
authors.forename: Stephen
authors.initials: S
authors.lastname: Margosiak
authors.forename: Victor
authors.initials: V
authors.lastname: Nikulin
authors.forename: James
authors.initials: J
authors.lastname: Levin
authors.forename: Kelly G
authors.initials: KG
authors.lastname: Sprankle
authors.forename: Martina E
authors.initials: ME
authors.lastname: Tedder
authors.forename: Robert
authors.initials: R
authors.lastname: Almassy
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Appelt
authors.forename: Kraig M
authors.initials: KM
authors.lastname: Yager
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D007191:Indazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009699:N-Glycosyl Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D009345:Neisseria meningitidis / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects; D013297:Streptococcus pyogenes / Q000187:drug effects; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C480610:3',4'-dichlorobiphenyl-3-sulfonic acid (3-chloro-7-isobutylamino-1H-indazol-5-yl)amide; D000900:Anti-Bacterial Agents; D007191:Indazoles; D013449:Sulfonamides; D009699:N-Glycosyl Hydrolases; C019606:adenosylhomocysteine nucleosidase