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 thei r ability to increase cutaneous vascular permeability following intrad ermal injection in dogs. A positive skin reaction was produced by the injection of a compound with a substituent of the piperazinyl, 4-piper izyl, 3-aminopyrolizinyl or 3-aminocyclobutyl group at the 7-position (C-7) of the quinolone skeleton at a minimum concentration of 101.8 mu g/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 pa rticular those with the 1-aminocyclopropyl group including T-3762 were barely positive in concentrations of more than 500 mu g/ml. An analys is of the three-dimensional models of the compounds with the C-7 subst ituted, nitrogen-containing groups revealed that the range of the geom etrically optimum distance between the nitrogen and the carbon atoms w as from 2.98 to 4.98 Angstrom for highly active compounds and from 2.4 7 to 2.65 Angstrom for weakly active compounds. In conclusion, the C-7 substituted piperazine moiety of the molecules of already-known fluor oquinolone antibiotics may be responsible for the ability to increase cutaneous vascular permeability; whereas T-3762 is practically inactiv e because the free amino nitrogen of the 1-aminocyclopropyl group is c onformationally present at a shorter distance from the carbon atom at position 7 of the ring nucleus.