N-(2-(arylmethylimino)ethyl)-7-chloroquinolin-4-amine derivatives, synthesized by thermal and ultrasonic means, are endowed with anti-Zika virus activity

Zika virus (ZIKV), an emerging Flavivirus, was recently associated with severe neurological complications and congenital diseases. Therefore, development of antiviral agents capable of inhibiting ZIKV replication is urgent. Chloroquine is a molecule with a confirmed safety history for use with pregn...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2017-02, Vol.127, p.434-441
Main Authors: Barbosa-Lima, Giselle, da Silveira Pinto, Ligia S., Kaiser, Carlos R., Wardell, James L., De Freitas, Caroline S., Vieira, Yasmine R., Marttorelli, Andressa, Cerbino Neto, José, Bozza, Patrícia T., Wardell, Solange M.S.V., de Souza, Marcus V.N., Souza, Thiago M.L.
Format: Article
Language:English
Subjects:
Animals
Antiviral Agents - chemical synthesis
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
Cercopithecus aethiops
Chloroquine - chemical synthesis
Chloroquine - chemistry
Chloroquine - pharmacology
Chloroquine - toxicity
Quinoline derivatives
Sonochemical method
Temperature
Ultrasonic Waves
Vero Cells
Virus Replication - drug effects
Zika virus
Zika Virus - drug effects
Zika Virus - physiology
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Summary:Zika virus (ZIKV), an emerging Flavivirus, was recently associated with severe neurological complications and congenital diseases. Therefore, development of antiviral agents capable of inhibiting ZIKV replication is urgent. Chloroquine is a molecule with a confirmed safety history for use with pregnant women, and has been found to exhibit anti-ZIKV activity at concentrations around 10 μM. This suggests that modifications to the chloroquine structure could be promising for obtaining more effective anti-ZIKV agents. Here, we report the ability of a series of N-(2-(arylmethylimino)ethyl)-7-chloroquinolin-4-amine derivatives to inhibit ZIKV replication in vitro. We have found that the quinoline derivative, N-(2-((5-nitrofuran-2-yl)methylimino)ethyl)-7-chloroquinolin-4-amine, 40, was the most potent compound within this series, reducing ZIKV replication by 72% at 10 μM. Compound 40 exhibits an EC50 value of 0.8 ± 0.07 μM, compared to that of chloroquine of 12 ± 3.2 μM. Good activities were also obtained for other compounds, including those with aryl groups = phenyl, 4-fluorophenyl, 4-nitrophenyl, 2,6-dimethoxyphenyl, 3-pyridinyl and 5-nitrothien-2-yl. Syntheses of these quinoline derivatives have been obtained both by thermal and ultrasonic means. The ultrasonic method produced comparable yields to the thermal (reflux) method in very much shorter times 30–180 s compared to 30–180 min reactions times. These results indicate that this group of compounds is a good follow-up point for the potential discovery of new drugs against the Zika disease. [Display omitted] •Chloroquine analogs show improved anti-Zika virus activity, compared to chloroquine.•Twenty analogos of chloroquine has been synthesize.•Analogs with C-4 modification were more potent than chloroquine against Zika virus replication.•Quinoline derivatives have been obtained both by thermal and ultrasonic means.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2017.01.007