| 摘要 |
The specification provides a therapeutic method for the treatment of a fungal infection comprising administering to a mammal afflicted with a fungal infection, particularly a systemic fungal infection, an effective antifungal amount of a compound of general formula (I) wherein: Ar is aryl or a nitrogen-, sulfur- or oxygen-containing heteroaromatic group; X is H, CN, CHO, OH, acetyl, CF3, O(C,-C4)alkyl, NO2, NH2, halogen or halo(C1-C4)alkyl; each Y is individually H, (C,-C4)alkyl or aralkyl; Y' is H, (C1- C4) alkyl, phenyl or methoxyphenyl; each Z is individually H, (C,-C4)alkyl, halogen or halo(C,-C4)alkyl; and n is 0 or 1; or a pharmaceutically acceptable salt thereof. According to one embodiment, Ar is phenyl, and X is Cl or Br, preferably occupying thepara position. As drawn, Z may occupy any position on the benzo moiety. Z is preferably H, halogen, CH3 or CF3. While a number of known inhibitors of human topoisomerase I were found to be ineffective against a fungal topoisomerase I, including nitidine and coralyne, the compounds of formula (I) are inhibitors of fungal topoisomerase I, as demonstrated by their ability to promote DNA cleavage in the presence of Aspergillus topoisomerase I. It was unexpectedly found that the Aspergillus enzyme is completely resistant to some of the most potent human topoisomerase I poisons such as nitidine and coralyne, and to the less potent mono-benzimidazole human topoisomerase I poisons. Furthermore, compounds of formula (I) also are cytotoxic to mammalian tumor cells, including camptothecin-sensitive and camptothecinresistant tumor cells and tumor cell lines exhibiting multi-drug resistance due to expression of the P-glycoprotein. Accordingly, there is provided a therapeutic method for the treatment of cancer comprising administering to a mammal (i.e. a human), an effective anticancer amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
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