Inhibition of Human Immunodeficiency Virus Type 1 Replication and Cytokine Production by Fluoroquinoline Derivatives

  1. Masanori Baba1,
  2. Mika Okamoto1,
  3. Masaki Kawamura1,
  4. Masahiko Makino1,
  5. Tomoe Higashida2,
  6. Tohru Takashi2,
  7. Youichi Kimura2,
  8. Tohru Ikeuchi2,
  9. Toshifumi Tetsuka3 and
  10. Takashi Okamoto3
  1. 1Division of Human Retroviruses, Center for Chronic Viral Diseases, Faculty of Medicine, Kagoshima University, Kagoshima 890, Japan (M.B., M.O., M.K., M.M.), 2New Product Research Laboratories, Daiichi Pharmaceutical Co., Ltd., Tokyo 134, Japan (T.H., T.Takashi, Y.K., T.I.) and 3Department of Molecular Genetics, Nagoya City University Medical School, Nagoya 467, Japan (T.Tetsuka, T.O.)

    Abstract

    We have recently identified 8-difluoromethoxy-1-ethyl-6-fluoro-1,4-dihydro-7-[4-(2-methoxyphenyl)-1-piperazinyl]-4-oxoquinoline-3-carboxylic acid (K-12) as a potent and selective inhibitor of human immunodeficiency virus type 1 (HIV-1) transcription. In the search for more effective derivatives and their mode of action, we have found 7-(3,4-dehydro-4-phenyl-1-piperidinyl)-1,4-dihydro-6-fluoro-1-methyl-8-trifluoromethyl-4-oxoquinoline-3-carboxylic acid (K-37) and 8-difluoromethoxy-1,4-dihydro-6-fluoro-7-(3,4-dehydro-4-phenyl-1-piperidinyl)1-[4,(1,2,4-triazol-1-yl)methylphenyl]-4-oxoquinoline-3-carboxylic acid (K-38) to be more potent inhibitors of HIV-1 replication than K-12. The EC50 values of K-37 and K-38 for HIV-1IIIB were 27 and 3.8 nm in peripheral blood mononuclear cells, respectively. These values were approximately 3- and 24-fold lower than the EC50 of K-12. K-38 was also a more potent inhibitor of HIV-1 replication in chronically infected cells, such as tumor necrosis factor α-stimulated OM-10.1 cells. K-37 and K-38 proved to be more cytotoxic than K-12 for a variety of cell lines as well as peripheral blood mononuclear cells. These compounds were more inhibitory of Tat-induced HIV-1 long terminal repeat-driven gene expression than K-12, which suggests that their mechanism of action is attributable in part to the inhibition of Tat function. Interestingly, K-37 and K-38 could suppress the production of tumor necrosis factor α and interleukin 6 in phytohemagglutinin-stimulated peripheral blood mononuclear cells and the expression of intercellular adhesion molecule 1 in tumor necrosis factor α-stimulated human umbilical vein endothelial cells at their nontoxic concentrations. In contrast, another K-12 derivative, 1,4-dihydro-8-dimethylaminomethyl-6-fluoro-7-[4-(2-methoxyphenyl)-1-piperadinyl]-1-methyl-4-oxoquinoline-3-carboxylic acid (K-42), had anti-HIV-1 activity and cytotoxicity profiles similar to those of K-12, but K-42 scarcely inhibited the cytokine production and intercellular adhesion molecule 1 expression.

    Footnotes

    • Send reprint requests to: Dr. Masanori Baba, Division of Human Retroviruses, Ctr for Chronic Viral Disease, Faculty of Medicine, Kagoshima University, 8–35-1, Sakuragaoka, Kagoshima 890, Japan. E-mail: baba{at}med3.kufm.kagoshima-u.ac.jp

    • This work was supported in part by the Japan Health Science Foundation.

    • Abbreviations:
      HIV-1
      human immunodeficiency virus type 1
      NF
      nuclear factor
      TNF-α
      tumor necrosis factor α
      LTR
      long terminal repeat
      NAC
      N-acetyl-l-cysteine
      K-12
      8-difluoromethoxy-1-ethyl-6-fluoro-1,4-dihydro-7-[4-(2-methoxyphenyl)-1-piperazinyl]-4-oxoquinoline-3-carboxylic acid
      IL
      interleukin
      ICAM
      intercellular adhesion molecule
      K-37
      7-(3,4-dehydro-4-phenyl-1-piperidinyl)-1,4-dihydro-6-fluoro-1-methyl-8-trifluoromethyl-4-oxoquinoline-3-carboxylic acid
      K-38
      8-difluoromethoxy-1,4-dihydro-6-fluoro-7-(3,4-dehydro-4-phenyl-1-piperidinyl)-1-[4,(1,2,4-triazol-1-yl)methylphenyl]-4-oxoquinoline-3-carboxylic acid
      K-42
      1,4-dihydro-8-dimethylaminomethyl-6-fluoro-7-[4-(2-methoxyphenyl)-1-piperazinyl]-1-methyl-4-oxoquinoline-3-carboxylic acid
      BTC
      5-methoxy-3-(1-methylethoxy)-benzo[b]thiophene-2-carboxamide
      PBMC
      peripheral blood mononuclear cell
      PHA
      phytohemagglutinin
      HUVEC
      human umbilical vein endothelial cell
      MTT
      3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
      CAT
      chloramphenicol acetyltransferase
      SI
      selectivity index
      HTLV-I
      human T-lymphotropic virus type I
      • Received December 29, 1997.
      • Accepted February 13, 1998.
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    1. Molecular Pharmacology June 1, 1998 vol. 53 no. 6 1097-1103
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