Design, Synthesis, Molecular Docking Analysis and Biological Evaluations of 4-[(Quinolin-4-yl)amino]benzamide Derivatives as Novel Anti-Influenza Virus Agents

Abstract

In this study, a series of 4-[(quinolin-4-yl)amino]benzamide derivatives as the novel anti-influenza agents were designed and synthesized. Cytotoxicity assay, cytopathic effect assay and plaque inhibition assay were performed to evaluate the anti-influenza virus A/WSN/33 (H1N1) activity of the target compounds. The target compound G07 demonstrated significant anti-influenza virus A/WSN/33 (H1N1) activity both in cytopathic effect assay (EC50 = 11.38 ± 1.89 µM) and plaque inhibition assay (IC50 = 0.23 ± 0.15 µM). G07 also exhibited significant anti-influenza virus activities against other three different influenza virus strains A/PR/8 (H1N1), A/HK/68 (H3N2) and influenza B virus. According to the result of ribonucleoprotein reconstitution assay, G07 could interact well with ribonucleoprotein with an inhibition rate of 80.65% at 100 µM. Furthermore, G07 exhibited significant activity target PA−PB1 subunit of RNA polymerase according to the PA−PB1 inhibitory activity prediction by the best pharmacophore Hypo1. In addition, G07 was well drug-likeness based on the results of Lipinski’s rule and ADMET prediction. All the results proved that 4-[(quinolin-4-yl)amino]benzamide derivatives could generate potential candidates in discovery of anti-influenza virus agents.

Novel Para-Aminobenzoic Acid Analogs and Their Potential Therapeutic Applications

“…For the evaluation of the anti-influenza activity of tested compounds, inhibition, cytotoxicity, and cytopathic assays were also carried out. The targeted compound benzamide possesses significant anti-influenza virus activity with both inhibition and cytopathic activity having IC 50 = 0.23 ± 0.15 µM and EC 50 = 11.38 ± 1.89 µM, respectively [110]. Significant activity against various influenza virus strains was also observed.…”

“…Quinolinyl aminobenzoic acids were prepared by a reaction of 4-chloroquinoline derivates with p-aminobenzoic acid by refluxing the mixture in ethanol. Desired quinoline analogs were synthesized by condensing quinolinyl-substituted aminobenzoic acid and amines [110] as shown in Scheme 5. The synthesis of innovative S-alkylphthalimidated and S-benzylated hybrids was achieved.…”

“…Scheme 5. Synthetic routes of derivatives of p-aminobenzoic acid having antiviral potential (adapted from ref [109][110][111]…”

Modular Biomimetic Strategy Enables Discovery and SAR Exploration of Oxime Macrocycles as Influenza A Virus (H1N1) Inhibitors

“…Not only did IAV cause high morbidity and mortality, but also it brings serious threat to the global public health, especially the widespread subtype H1N1, which caused quite serious pandemics in both 1918 and 2009, and successive epidemics until now. − Seasonal influenza vaccination still remains the prevalent prophylactic means for controlling IAV infections. However, its efficacy is remarkably less effective for individuals with compromised immunity and its availability is highly dependent on the accurate forecast of the circulating strains. − Besides, small molecules offer an important therapeutic option to prevent and treat influenza. ,− Until now, Food and Drug Administration has approved three major types of antivirals with different mechanisms of action (MOAs), including M2 ion-channel blockers, neuraminidase inhibitors (NAIs), and RNA-dependent RNA polymerase (RdRp) inhibitors (Figure A). − It should be noted that the representative M2 ion-channel blockers (amantadine and rimantadine) are not recommended anymore due to the ineffectiveness against circulating influenza strains . Although oseltamivir as an NAI can be administrated orally and exhibits broad-spectrum antiviral potencies, the emergence of resistance undermines its efficacy. ,− Therefore, it is highly urgent and desirable to develop more effective, nontoxic, structurally novel antivirals with alternative targets.…”