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Abstract Antiretroviral therapy (ART) against HIV-1 infection offers the promise of controlling disease progression and prolonging the survival of HIV-1-infected patients. However, even the most potent ART regimens available today cannot cure HIV-1. Because patients will be exposed to ART for many years, physicians and researchers must anticipate the emergence of drug-resistant HIV-1, potential adverse effects of the current drugs, and need for future drug development. In this study, we screened a small-molecule compound library using cell-based anti-HIV-1 assays and discovered a series of novel anti-HIV-1 compounds, 4-oxoquinolines. These compounds exhibited potent anti-HIV-1 activity (EC 50 < 0.1 μM) with high selectivity indexes (CC 50 /EC 50 > 2500) and favorable pharmacokinetic profiles in mice. Surprisingly, our novel compounds have a chemical backbone similar to the clinically used integrase (IN) strand transfer inhibitor (INSTI) elvitegravir, although they lack the crucial 3-carboxylate moiety needed for the common INSTI diketo motif. Indeed, the new 4-oxoquinoline derivatives have no detectable INSTI activity. In addition, various drug-resistant HIV-1 strains did not display cross resistance to these compounds. Interestingly, time-of-addition experiments indicated that the 4-oxoquinoline derivative remains its anti-HIV-1 activity even after the viral integration stage. Furthermore, the compounds significantly suppressed p24 antigen production in HIV-1 latently infected cells exposed with tumor necrosis factor alpha. These findings suggest that our 4-oxoquinoline derivatives with no 3-carboxylate moiety may become novel lead compounds in the development of anti-HIV-1 drugs. Highlights • We screened a small-molecule compound library using cell-based anti-HIV-1 assays. • We identified novel compounds, 4-oxoquinolines, that exhibit potent anti-HIV-1 activity and no detectable INSTI effect. • The compounds lack the 3-carboxylate moiety required for the diketo motif common in HIV-1 INSTIs. • Various drug-resistant HIV-1 strains did not display cross resistance to these compounds. • These 4-oxoquinoline derivatives represent novel lead compounds in the development of anti-HIV-1 drugs. [ABSTRACT FROM AUTHOR]

We described the synthesis of a new congener series of 1,2,3-triazolyl-4-oxoquinolines and evaluated their ability to inhibit oseltamivir (OST)-resistant influenza strains. Oxoquinoline derivative 1i was the most potent compound within this series, inhibiting 94% of wild-type (WT) influenza neuraminidase (NA) activity. Compound 1i inhibited influenza virus replication with an EC 50 of 0.2 μM with less cytotoxicity than OST, and also inhibited different OST-resistant NAs. These results suggest that 1,2,3-triazolyl-4-oxoquinolines represent promising lead molecules for further anti-influenza drug design. [ABSTRACT FROM AUTHOR]

We have achieved the synthesis of 1-aryl-2-substituted 4-oxoquinoline and 4-oxo-1,8-naphthyridine derivatives, which cannot be synthesized by known methods, via two useful synthons, 2-formyl-4-oxoquinoline and 2-methylsulfonyl-4-oxo-1,8-naphthyridine. We also succeeded in the synthesis of 1-aryl-3-fluoro-4- oxoquinoline by fluorocyclization of N-arylenaminone with Selectfluor ® and potassium carbonate in DMF in a one-pot procedure. To the best of our knowledge, this is the first synthesis of 3-fluoro-4- oxoquinoline derivatives. We confirmed that these protocols were mutually applicable to the synthesis of 4-oxoquinoline and 4-oxo- 1,8-naphthyridine derivatives. [ABSTRACT FROM AUTHOR]