Structure-based design, synthesis, and antimicrobial activity of indazole-derived SAH/MTA nucleosidase inhibitors.
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.
Li
Xiaoming
X
Department of Medicinal Chemistry, Quorex Pharmaceuticals, 1890 Rutherford Drive, Carlsbad, CA 92008, USA.
Chu
Sam
S
Feher
Victoria A
VA
Khalili
Mitra
M
Nie
Zhe
Z
Margosiak
Stephen
S
Nikulin
Victor
V
Levin
James
J
Sprankle
Kelly G
KG
Tedder
Martina E
ME
Almassy
Robert
R
Appelt
Krzysztof
K
Yager
Kraig M
KM
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
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