Structure-activity relationships of 3-aminoquinazolinediones, a new class of bacterial type-2 topoisomerase (DNA gyrase and topo IV) inhibitors.
A series of 3-aminoquinazolinediones was synthesized and evaluated for its antibacterial and DNA gyrase activity. The SAR around the quinazolinedione core was explored and the optimal substitutions were combined to give two compounds, 2r and 2s, with exceptional enzyme potency (IC50 = 0.2 microM) and activity against gram-positive organisms (MIC's = 0.015-0.06 microg/mL).
Tran
Tuan P
TP
Department of Chemistry, Pfizer Global Research and Development, Ann Arbor Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. tuan.tran@pfizer.com
Ellsworth
Edmund L
EL
Sanchez
Joseph P
JP
Watson
Brian M
BM
Stier
Michael A
MA
Showalter
H D Hollis
HD
Domagala
John M
JM
Shapiro
Martin A
MA
Joannides
E Themis
ET
Gracheck
Stephen J
SJ
Nguyen
Dai Q
DQ
Bird
Paul
P
Yip
Judy
J
Sharadendu
Anurag
A
Ha
Chan
C
Ramezani
Saeed
S
Wu
Xiujuan
X
Singh
Rajeshwar
R
D000588:Amines / Q000737:chemistry / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry; D027081:DNA Gyrase; D006094:Gram-Positive Bacteria / Q000187:drug effects; D020128:Inhibitory Concentration 50; D052999:Quinazolinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
D000588:Amines; D000900:Anti-Bacterial Agents; D052999:Quinazolinones; D059005:Topoisomerase II Inhibitors; D027081:DNA Gyrase