SAR-Based Optimization of a 4-Quinoline Carboxylic Acid Analogue with Potent Antiviral Activity

Das, Priyabrata; Deng, Xingming; Zhang, Liang; Roth, Michael G.; Fontoura, Beatriz M. A.; Phillips, Margaret A.; Brabander, Jef K. De

doi:10.1021/ml300464h

Cited by 56 publications

(63 citation statements)

References 25 publications

(54 reference statements)

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“…29 The data obtained for compound 3e was consistent with the literature. The reaction mixture was refluxed for 24 h. It was then cooled to room temperature, and ethanol was removed under reduced pressure.…”

Section: Methodssupporting

confidence: 87%

Investigation of quinoline-4-carboxylic acid as a highly potent scaffold for the development of alkaline phosphatase inhibitors: synthesis, SAR analysis and molecular modelling studies

et al. 2015

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The role played by organic chemistry in the pharmaceutical industry continues to be one of the main drives in the drug discovery process. More than ever, the industry demands from organic chemists the development of small molecules, which could be a rich source of biological potential. In this context, a diverse range of quinoline-4-carboxylic acid derivatives has been synthesized and evaluated as potent inhibitors of alkaline phosphatases. The structural build-up

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Section: Methodssupporting

confidence: 87%

Investigation of quinoline-4-carboxylic acid as a highly potent scaffold for the development of alkaline phosphatase inhibitors: synthesis, SAR analysis and molecular modelling studies

et al. 2015

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“…14,34 The additional truncations relative to constructs used for IC 50 determination were found to improve crystal diffraction while not affecting enzyme activity ( k cat and K m ). Two expression plasmids for rat DHODH were tested in crystallographic studies.…”

Section: Methodsmentioning

confidence: 98%

Fluorine Modulates Species Selectivity in the Triazolopyrimidine Class of Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors

et al. 2014

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Malaria is one of the most serious global infectious diseases. The pyrimidine biosynthetic enzyme Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) is an important target for antimalarial chemotherapy. We describe a detailed analysis of protein–ligand interactions between DHODH and a triazolopyrimidine-based inhibitor series to explore the effects of fluorine on affinity and species selectivity. We show that increasing fluorination dramatically increases binding to mammalian DHODHs, leading to a loss of species selectivity. Triazolopyrimidines bind Plasmodium and mammalian DHODHs in overlapping but distinct binding sites. Key hydrogen-bond and stacking interactions underlying strong binding to PfDHODH are absent in the mammalian enzymes. Increasing fluorine substitution leads to an increase in the entropic contribution to binding, suggesting that strong binding to mammalian DHODH is a consequence of an enhanced hydrophobic effect upon binding to an apolar pocket. We conclude that hydrophobic interactions between fluorine and hydrocarbons provide significant binding energy to protein–ligand interactions. Our studies define the requirements for species-selective binding to PfDHODH and show that the triazolopyrimidine scaffold can alternatively be tuned to inhibit human DHODH, an important target for autoimmune diseases.

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“…Pyrimidines such as uridine and cytidine were able to revert the inhibitory activity of compound 13 . Subsequent SAR studies based on compound 13 yielded compound 14 , which showed drastically increased activity against A/WSN/33 [103]. The structural similarity between compound 14 and RK424 suggests that such compounds might target multiple targets at the same time, which explains their potent efficacy.…”

Section: Inhibitors Targeting Influenza a Virus Npmentioning

confidence: 99%

Influenza A Virus Nucleoprotein: A Highly Conserved Multi-Functional Viral Protein as a Hot Antiviral Drug Target

Sneyd

Dekant

et al. 2017

CTMC

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Prevention and treatment of influenza virus infection is an ongoing unmet medical need. Each year, thousands of deaths and millions of hospitalizations are attributed to influenza virus infection, which poses a tremendous health and economic burden to the society. Aside from the annual influenza season, influenza viruses also lead to occasional influenza pandemics as a result of emerging or re-emerging influenza strains. Influenza viruses are RNA viruses that exist in quasispecies, meaning that they have a very diverse genetic background. Such a feature creates a grand challenge in devising therapeutic intervention strategies to inhibit influenza virus replication, as a single agent might not be able to inhibit all influenza virus strains. Both classes of currently approved anti-influenza drugs have limitations: the M2 channel blockers amantadine and rimantadine are no longer recommended for use in the U.S. due to predominant drug resistance, and resistance to the neuraminidase inhibitor oseltamivir is continuously on the rise. In pursuing the next generation of antiviral drugs with broad-spectrum activity and higher genetic barrier of drug resistance, the influenza virus nucleoprotein (NP) stands out as a high-profile drug target. This review summarizes recent developments in designing inhibitors targeting influenza NP and their mechanisms of action.

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SAR-Based Optimization of a 4-Quinoline Carboxylic Acid Analogue with Potent Antiviral Activity

Cited by 56 publications

References 25 publications

Investigation of quinoline-4-carboxylic acid as a highly potent scaffold for the development of alkaline phosphatase inhibitors: synthesis, SAR analysis and molecular modelling studies

Investigation of quinoline-4-carboxylic acid as a highly potent scaffold for the development of alkaline phosphatase inhibitors: synthesis, SAR analysis and molecular modelling studies

Fluorine Modulates Species Selectivity in the Triazolopyrimidine Class of Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors

Influenza A Virus Nucleoprotein: A Highly Conserved Multi-Functional Viral Protein as a Hot Antiviral Drug Target

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