@article {Baba1097, author = {Masanori Baba and Mika Okamoto and Masaki Kawamura and Masahiko Makino and Tomoe Higashida and Tohru Takashi and Youichi Kimura and Tohru Ikeuchi and Toshifumi Tetsuka and Takashi Okamoto}, title = {Inhibition of Human Immunodeficiency Virus Type 1 Replication and Cytokine Production by Fluoroquinoline Derivatives}, volume = {53}, number = {6}, pages = {1097--1103}, year = {1998}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, 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. The American Society for Pharmacology and Experimental Therapeutics}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/53/6/1097}, eprint = {https://molpharm.aspetjournals.org/content/53/6/1097.full.pdf}, journal = {Molecular Pharmacology} }