Synthesis and antiviral activity of thiosemicarbazone derivatives of pyridazinecarbaldehydes and alkyl pyridazinyl ketones.
Various novel thiosemicarbazones (TSCs) 15b-e, 16b-e, 17b-e, 18b-e, and 19b-e derived from 4-pyridazinecarbaldehyde, 3-pyridazinecarbaldehyde, 4-acetylpyridazine, 3-acetylpyridazine, and 3-propionylpyridazine were prepared and their cytotoxic and antiherpetic potentials were evaluated. It was found that the replacement of the 2-pyridylmoiety in aldehyde derived compounds 20a-c by a 4-pyridazinyl group (compounds 15b-d) abolishes biological activity. However, in TSCs derived from 3-pyridazinecarbaldehyde (16b-d) the cytotoxic potency was considerably reduced (factor approximately 300), while the antiviral activity was largely retained. A total loss of biological activity occurred when the pyridyl group in TSC 20d, derived from 2-acetylpyridine, was replaced by the 4-pyridazinyl system (17d). By employment of the 3-pyridazinyl unit for isosteric modification, however, the cell toxicity could be reduced significantly (factor 100) without impairing the antiherpetic potential also in the series of TSCs derived from N-heteroaromatic ketones. It was observed that there is no obvious influence of the size of the cycloamino substituent on the biological activities in compounds 20a-d, 15b-d, 16b-d, 17b-d, and 18b-d. While the pyridine derived TSCs in our experiments proved clearly cytotoxic at lower concentrations than those being antivirally active, the aza-analogous compounds derived from 3-acetylpyridazine (18b-e) inhibited plaque formation at concentrations equal to those causing cytotoxic effects.(ABSTRACT TRUNCATED AT 250 WORDS)
Easmon
J
J
Department of Drug Analysis, University of Vienna, Austria.
Heinisch
G
G
Holzer
W
W
Rosenwirth
B
B
D000447:Aldehydes / Q000138:chemical synthesis / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis*; D002470:Cell Survival / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D007659:Ketones / Q000138:chemical synthesis / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology; D012995:Solubility; D013055:Spectrophotometry, Infrared; D013882:Thiosemicarbazones / Q000138:chemical synthesis* / Q000494:pharmacology; D010948:Viral Plaque Assay
D000447:Aldehydes; D000998:Antiviral Agents; D007659:Ketones; D011724:Pyridazines; D013882:Thiosemicarbazones