Isothiazoloquinolones with enhanced antistaphylococcal activities against multidrug-resistant strains: effects of structural modifications at the 6-, 7-, and 8-positions.
We describe the biological evaluation of isothiazoloquinolones (ITQs) having structural modifications at the 6-, 7-, and 8-positions. Addition of a methoxy substituent to C-8 effected an increase in antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and a decrease in cytotoxic activity against Hep2 cells. Removal of fluorine from C-6 or replacement of the C-8 carbon with a nitrogen compromised anti-MRSA activity. When the groups attached at C-7 were compared, the anti-MRSA activity decreased in the order 6-isoquinolinyl > 4-pyridinyl > 5-dihydroisoindolyl > 6-tetrahydroisoquinolinyl. The compound with the most desirable in vitro biological profile was 9-cyclopropyl-6-fluoro-8-methoxy-7-(2-methylpyridin-4-yl)-9H-isothiazolo[5,4-b]quinoline-3,4-dione (7g). This ITQ demonstrated (i) strong in vitro anti-MRSA activity (MIC90 = 0.5 microg/mL), (ii) strong inhibitory activities against S. aureus DNA gyrase and topoisomerase IV, with weak activity against human topoisomerase II, (iii) weak cytotoxic activities against three cell lines, and (iv) efficacy in an in vivo murine thigh model of infection employing MRSA.
Wang
Qiuping
Q
Achillion Pharmaceuticals, Inc., 300 George Street, New Haven, Connecticut 06511, USA.
Lucien
Edlaine
E
Hashimoto
Akihiro
A
Pais
Godwin C G
GC
Nelson
David M
DM
Song
Yongsheng
Y
Thanassi
Jane A
JA
Marlor
Christopher W
CW
Thoma
Christy L
CL
Cheng
Jijun
J
Podos
Steven D
SD
Ou
Yangsi
Y
Deshpande
Milind
M
Pucci
Michael J
MJ
Buechter
Douglas D
DD
Bradbury
Barton J
BJ
Wiles
Jason A
JA
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D024901:Drug Resistance, Multiple, Bacterial; D005260:Female; D006801:Humans; D016106:Methicillin Resistance; D051379:Mice; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors
C517801:9-cyclopropyl-6-fluoro-8-methoxy-7-(2-methylpyridin-4-yl)-9H-isothiazolo(5,4-b)quinoline-3,4-dione; D000900:Anti-Bacterial Agents; D015363:Quinolones; D013844:Thiazoles; D059005:Topoisomerase II Inhibitors