Pharmacological Properties of T-3762, a Novel Fluoroquinolone Antimicrobial Agent in Parenteral Use. III. Chemical Structures and Dermovascular Permeability-Increasing Activities

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Fluoroquinolone antibiotics and chemically related compounds in cluding 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 μg/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 μg/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 Å for highly active compounds and from 2.47 to 2.65 Å 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.