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
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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
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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.
- The American Society for Pharmacology and Experimental Therapeutics
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