Pharmacological properties of T-3762, a novel fluoroquinolone antimicrobial agent in parenteral use. III. Chemical structures and dermovascular permeability-increasing activities.
Fluoroquinolone antibiotics and chemically related compounds including the pazufloxacin methanesulfonate named T-3762 were examined for their ability to increase cutaneous vascular permeability following intradermal injection in dogs. A positive skin reaction was produced by the injection of a compound with a substituent of the piperazinyl, 4-piperizyl, 3-aminopyrolizinyl or 3-aminocyclobutyl group at the 7-position (C-7) of the quinolone skeleton at a minimum concentration of 101.8 microg/ml or less. Substitution at position 1, 6 or 8 of the ring nucleus hardly affected the activity of the compounds with the C-7 substituted piperazinyl group. The compounds with 7-positioned substituents other than the piperazinyl group showed relatively weak activity, and in particular those with the 1-aminocyclopropyl group including T-3762 were barely positive in concentrations of more than 500 microg/ml. An analysis of the three-dimensional models of the compounds with the C-7 substituted, nitrogen-containing groups revealed that the range of the geometrically optimum distance between the nitrogen and the carbon atoms was from 2.98 to 4.98 A for highly active compounds and from 2.47 to 2.65 A for weakly active compounds. In conclusion, the C-7 substituted piperazine moiety of the molecules of already-known fluoroquinolone antibiotics may be responsible for the ability to increase cutaneous vascular permeability, whereas T-3762 is practically inactive because the free amino nitrogen of the 1-aminocyclopropyl group is conformationally present at a shorter distance from the carbon atom at position 7 of the ring nucleus.
Research Laboratories, Toyama Chemical Co., Ltd., Shimookui, Japan.
K
K
Furuhata
Y
Y
Todo
T
T
Takakura
Y
Y
Watanabe
H
H
Narita
D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects*; D004285:Dogs; D005260:Female; D024841:Fluoroquinolones; D007271:Injections, Intradermal; D008297:Male; D008958:Models, Molecular; D012867:Skin / Q000098:blood supply*; D013329:Structure-Activity Relationship
D000890:Anti-Infective Agents; D024841:Fluoroquinolones; C113785:T 3762