Anti‐influenza Drug Discovery: Identification of an Orally Bioavailable Quinoline Derivative through Activity‐ and Property‐Guided Lead Optimization

Yeh, Jiann Yih; Coumar, Mohane Selvaraj; Shiao, Hui Yi; Lin, Ta Jen; Lee, Yen‐Chun; Hung, Hui Chen; Ko, Shengkai; Kuo, Fu Ming; Fang, Ming-Yu; Huang, Yi-Hsiang; Hsu, Ju Wei; Yeh, Teng Kuang; Shih, Shin Ru; Chao, Yu Sheng; Horng, Jim-Tong; Hsieh, Hsing Pang

doi:10.1002/cmdc.201200259

Cited by 6 publications

(3 citation statements)

References 47 publications

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“…Next, the DFG-in-modeled structure was used to perform virtual screening (VS) of an in-house compound database (125,000 compounds; obtained from ChemDiversity, http://www.chemdiv.com ) using Dock 6.0. We have successfully used this chemically diverse library both for high-throughput screening as well as VS campaign for different targets, including, for influenza 29 30 , EGFR kinase 31 , aurora kinase 32 33 , tubulin target 34 etc. The screening parameters were the same as those used in the docking study of the clinical trial drugs.…”

Section: Resultsmentioning

confidence: 99%

Homology modeling of DFG-in FMS-like tyrosine kinase 3 (FLT3) and structure-based virtual screening for inhibitor identification

Singh

Coumar

et al. 2015

Sci Rep

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The inhibition of FMS-like tyrosine kinase 3 (FLT3) activity using small-molecule inhibitors has emerged as a target-based alternative to traditional chemotherapy for the treatment of acute myeloid leukemia (AML). In this study, we report the use of structure-based virtual screening (SBVS), a computer-aided drug design technique for the identification of new chemotypes for FLT3 inhibition. For this purpose, homology modeling (HM) of the DFG-in FLT3 structure was carried using two template structures, including PDB ID: 1RJB (DFG-out FLT3 kinase domain) and PDB ID: 3LCD (DFG-in CSF-1 kinase domain). The modeled structure was able to correctly identify known DFG-in (SU11248, CEP-701, and PKC-412) and DFG-out (sorafenib, ABT-869 and AC220) FLT3 inhibitors, in docking studies. The modeled structure was then used to carry out SBVS of an HTS library of 125,000 compounds. The top scoring 97 compounds were tested for FLT3 kinase inhibition, and two hits (BPR056, IC50 = 2.3 and BPR080, IC50 = 10.7 μM) were identified. Molecular dynamics simulation and density functional theory calculation suggest that BPR056 (MW: 325.32; cLogP: 2.48) interacted with FLT3 in a stable manner and could be chemically optimized to realize a drug-like lead in the future.

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Section: Resultsmentioning

confidence: 99%

Homology modeling of DFG-in FMS-like tyrosine kinase 3 (FLT3) and structure-based virtual screening for inhibitor identification

Singh

Coumar

et al. 2015

Sci Rep

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“…BPR3P0128 is a synthetic analog that was also derived from SAR studies of an HTS hit (Table 3) [104, 105]. BPR3P0128 inhibited the early stage of viral replication by targeting the PB2-associated cap-snatching function, which is required for transcribing viral mRNA from vRNA.…”

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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“…Although a number of different classes of natural compounds have been studied for their anti‐H5N1 activity, no quinolone alkaloids have been investigated as agents against avian influenza . Recently, quinoline‐based compounds were reported to show antiviral properties,, and thus, in the context of the above‐mentioned facts, 8‐hydroxyquinoline‐2‐carboxanilides were subjected to the primary screening on anti‐avian influenza activity.…”

Section: Introductionmentioning

confidence: 99%

8‐Hydroxyquinoline‐2‐Carboxanilides as Antiviral Agents Against Avian Influenza Virus

Kos

Kapustíková

et al. 2019

ChemistrySelect

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Series of thirty‐two mono‐, di‐ and tri‐substituted 8‐hydroxyquinoline‐2‐carboxanilides were prepared by microwave‐assisted synthesis. The compounds were characterized, and their lipophilicity was experimentally determined. Primary in vitro screening of the cytotoxicity of all the synthesized compounds was performed using adenocarcinomic human alveolar basal epithelial cells (A549), and determined nontoxic compounds were then tested for their activity against highly pathogenic H5N1 avian influenza virus. 8‐Hydroxy‐N‐(3,4,5‐trichlorophenyl)quinoline‐2‐carboxamide, N‐(3‐chloro‐2‐fluorophenyl)‐8‐hydroxyquinoline‐2‐carboxamide and N‐(3,4‐dichlorophenyl)‐8‐hydroxyquinoline‐2‐carboxamide demonstrated the highest activity within the investigated series (IC50 = 11.3, 21.2 and 31.2 μM, respectively), while N‐(4‐chloro‐2‐fluorophenyl)‐8‐hydroxyquinoline‐2‐carboxamide expressed the highest cytotoxic effect (CC50 = 31.6 μM). In general, the inhibitory activity of the compounds depends on the position of halogen substituents on the anilide ring and is also affected by the lipophilicity and electron properties of individual substituents of the anilide part of the molecule. The structure‐activity relationships are discussed.

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Anti‐influenza Drug Discovery: Identification of an Orally Bioavailable Quinoline Derivative through Activity‐ and Property‐Guided Lead Optimization

Cited by 6 publications

References 47 publications

Homology modeling of DFG-in FMS-like tyrosine kinase 3 (FLT3) and structure-based virtual screening for inhibitor identification

Homology modeling of DFG-in FMS-like tyrosine kinase 3 (FLT3) and structure-based virtual screening for inhibitor identification

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

8‐Hydroxyquinoline‐2‐Carboxanilides as Antiviral Agents Against Avian Influenza Virus

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