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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]

As part of a continuing search for new potential anticancer candidates, we describe the synthesis, cytotoxicity and mechanistic evaluation of a series of 4-oxoquinoline-3-carboxamide derivatives as novel anticancer agents. The inhibitory activity of compounds 10–18 was determined against three cancer cell lines using the MTT colorimetric assay. The screening revealed that derivatives 16b and 17b exhibited significant cytotoxic activity against the gastric cancer cell line but was not active against a normal cell line, in contrast to doxorubicin, a standard chemotherapeutic drug in clinical use. Interestingly, no hemolytical activity was observed when the toxicity of 16b and 17b was tested against blood cells. The in silico and in vitro mechanistic evaluation indicated the potential of 16b as a lead for the development of novel anticancer agents against gastric cancer cells.

• Compounds 15a-k were synthesized as antitumoral agents. • 15c, 15e , 15g, and 15k showed significant cytotoxicity. • 15c, g , and k increased the levels of reactive species and superoxide ions. • In silico toxicity screening showed that 15g presented low hepatotoxicity risk. • 15g is a potential candidate to optimize for the development of anticancer agents. Breast cancer is the leading cause of cancer death in women. Although the available treatments are efficient, cancer cells promptly develop resistance to different drugs, leading to disease relapse and promoting tumor progression. Here, novel 4-oxoquinoline-3-carboxamide acyclonucleoside phosphonate hybrids were synthesized as antitumoral agents, and in silico toxicity screening were performed. Derivatives 15c, 15e , 15g, and 15k showed significant cytotoxicity where 15c induces the most considerable loss of cell viability through the apoptotic process, while 15k induces cell death by necrosis. All compounds, except 15e , induced the production of OH- and NO, besides increasing the levels of superoxide ions. In silico toxicity studies showed that 15g presented low hepatotoxicity risk and probability as BCRP substrate. These findings point out that derivative 15g is a potential candidate for an optimization program for the development of new anticancer agents. [Display omitted] [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]

As part of a continuing search for new potential anticancer candidates, we describe the synthesis, cytotoxicity and mechanistic evaluation of a series of 4-oxoquinoline-3-carboxamide derivatives as novel anticancer agents. The inhibitory activity of compounds 10-18 was determined against three cancer cell lines using the MTT colorimetric assay. The screening revealed that derivatives 16b and 17b exhibited significant cytotoxic activity against the gastric cancer cell line but was not active against a normal cell line, in contrast to doxorubicin, a standard chemotherapeutic drug in clinical use. Interestingly, no hemolytical activity was observed when the toxicity of 16b and 17b was tested against blood cells. The in silico and in vitro mechanistic evaluation indicated the potential of 16b as a lead for the development of novel anticancer agents against gastric cancer cells. [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]

Human immunodeficiency virus type 1 (HIV-1) is a public health problem that affects over 38 million people worldwide. Although there are highly active antiretroviral therapies, emergence of antiviral resistant strains is a problem which leads to almost a million death annually. Thus, the development of new drugs is necessary. The viral enzyme reverse transcriptase (RT) represents a validated therapeutic target. Because the oxoquinolinic scaffold has substantial biological activities, including antiretroviral, a new series of 4-oxoquinoline ribonucleoside derivatives obtained by molecular hybridization were studied here. All synthesized compounds were tested against human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT), and 9a and 9d displayed the highest antiviral activities, with IC 50 values of 1.4 and 1.6 μM, respectively. These compounds were less cytotoxic than AZT and showed CC 50 values of 1486 and 1394 μM, respectively. Molecular docking studies showed that the most active compounds bound to the allosteric site of the enzyme, suggesting a low susceptibility to the development of antiviral resistance. In silico pharmacokinetic and toxicological evaluations reinforced the potential of the active compounds as anti-HIV candidates for further exploration. Overall, this work showed that compounds 9a and 9d are promising scaffold for future anti-HIV-1 RT drug design., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

A series of pyrrolo[2,3- b ]pyridine derivatives bearing 4-oxoquinoline moiety were designed, synthesized and evaluated for the anti-proliferative on three cancer cell lines (A549, HepG2 and MCF-7) in vitro. Most of the compounds showed moderate to high potency. Some excellent compounds were tested for the inhibitory activity of c-Met kinase. Compound 34 (c-Met IC 50 = 17 nM) was investigated the selectivity against Flt-3, c-Kit, VEGFR-2, ALK, PDGFR-β and RON. Structure-activity relationship studies indicated that hydrogen, fluorine atom, and mono-electron-withdrawing groups (mono-EWGs, such as R2 = F) on R, R1 and R2, respectively, were beneficial for the anti-proliferative activities of the target compounds. Besides, we have took further study on the combined mode between compound 34 and c-Met kinase through molecular docking. [ABSTRACT FROM AUTHOR]