Hybrid antibacterials. DNA polymerase-topoisomerase inhibitors.
Novel Gram-positive (Gram+) antibacterial compounds consisting of a DNA polymerase IIIC (pol IIIC) inhibitor covalently connected to a topoisomerase/gyrase inhibitor are described. Specifically, 3-substituted 6-(3-ethyl-4-methylanilino)uracils (EMAUs) in which the 3-substituent is a fluoroquinolone moiety (FQ) connected by various linkers were synthesized. The resulting "AU-FQ" hybrid compounds were significantly more potent than the parent EMAU compounds as inhibitors of pol IIIC and were up to 64-fold more potent as antibacterials in vitro against Gram+ bacteria. The hybrids inhibited the FQ targets, topoisomerase IV and gyrase, with potencies similar to norfloxacin but 10-fold lower than newer agents, for example, ciprofloxacin and sparfloxacin. Representative hybrids protected mice from lethal Staphylococcus aureus infection after intravenous dosing, and one compound showed protective effect against several antibiotic-sensitive and -resistant Gram+ infections in mice. The AU-FQ hybrids are a promising new family of antibacterials for treatment of antibiotic-resistant Gram+ infections.
GLSynthesis Inc., One Innovation Drive, Worcester, Massachusetts 01605, USA.
Chengxin
C
Zhi
Zheng-Yu
ZY
Long
Andrzej
A
Manikowski
Jeanne
J
Comstock
Wei-Chu
WC
Xu
Neal C
NC
Brown
Paul M
PM
Tarantino
Karsten A
KA
Holm
Edward J
EJ
Dix
George E
GE
Wright
Marjorie H
MH
Barnes
Michelle M
MM
Butler
Kimberly A
KA
Foster
William A
WA
LaMarr
Benoit
B
Bachand
Richard
R
Bethell
Caroline
C
Cadilhac
Sylvie
S
Charron
Serge
S
Lamothe
Irina
I
Motorina
Richard
R
Storer
D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D004258:DNA Polymerase III / Q000037:antagonists & inhibitors*; D024881:Drug Resistance, Bacterial; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D008297:Male; D051379:Mice; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors; D023382:Toxicity Tests, Acute; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
D000814:Aniline Compounds; D000900:Anti-Bacterial Agents; D059005:Topoisomerase II Inhibitors; D014498:Uracil; D004258:DNA Polymerase III