Research paper N-(2-(arylmethylimino)ethyl)-7-chloroquinolin-4-amine derivatives, synthesized by thermal and ultrasonic means, are endowed with anti- Zika virus activity Giselle Barbosa-Lima a, b, c, 1 , Ligia S. da Silveira Pinto d, 1 , Carlos R. Kaiser d , James L. Wardell e, f , Caroline S. De Freitas a, b , Yasmine R. Vieira a, b, c , Andressa Marttorelli a, b , Jos  e Cerbino Neto c , Patrícia T. Bozza a , Solange M.S.V. Wardell g , Marcus V.N. de Souza d, e, *, 2 , Thiago M.L. Souza a, b, c, 2 a Instituto Oswaldo Cruz, Fiocruz - Fundaç~ ao Oswaldo Cruz, Rio de Janeiro, Brazil b Centro de Desenvolvimento Tecnol ogico em Saúde, Fiocruz - Fundaç~ ao Oswaldo Cruz, Rio de Janeiro, Brazil c Instituto Nacional de Infectologia Evandro Chagas, Fiocruz - Fundaç~ ao Oswaldo Cruz, Rio de Janeiro, Brazil d Departamento de Química Org^ anica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil e Instituto de Tecnologia em F armacos - Far-Manguinhos, Fiocruz - Fundaç~ ao Oswaldo Cruz, Rio de Janeiro, Brazil f Department of Chemistry, University of Aberdeen, Old Aberdeen, Scotland, UK g CHEMSOL, 1 Harcourt Road, Aberdeen AB15 5 NY, Scotland, UK article info Article history: Received 24 October 2016 Received in revised form 4 January 2017 Accepted 5 January 2017 Available online 6 January 2017 Keywords: Zika virus Quinoline derivatives Sonochemical method abstract 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 mM. This suggests that modi- fications 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 de- rivatives 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 mM. Compound 40 exhibits an EC 50 value of 0.8 ± 0.07 mM, compared to that of chloroquine of 12 ± 3.2 mM. Good activities were also obtained for other compounds, including those with aryl groups ¼ 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 30e180 s compared to 30e180 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. © 2017 Elsevier Masson SAS. All rights reserved. 1. Introduction Quinolinyl derivatives are found in many synthetic and natural products possessing a wide range of biological and pharmacological activities. In particular, quinolinyl derivatives have found impor- tance over many years in antimalarial drug research [1e3]. Many of these quinolinyl compounds have subsequently been used as starting points for research in other medical areas, including as antituberculosis [4,5], anticancer [6e11] and, more recently, as anti-Zika virus (ZIKV) agents [12]. ZIKV is a Flavivirus, which belongs to the Flaviviridae family. This family includes other agents of clinical significance, such as dengue (DENV), West Nile (WNV) and Japanese encephalitis (JEV) viruses. * Corresponding author. Instituto de Tecnologia em F armacos-Far-Manguinhos, FioCruz-Fundaç~ ao Oswaldo Cruz, P.O. Box: 21041-250, Rio de Janeiro, Brazil. Tel.: þ55 2139772404; fax: þ55 2125602518. E-mail address: marcos_souza@far.fiocruz.br (M.V.N. de Souza). 1 These authors contributed equally as first author. 2 These authors contributed equally as last author. Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech http://dx.doi.org/10.1016/j.ejmech.2017.01.007 0223-5234/© 2017 Elsevier Masson SAS. All rights reserved. European Journal of Medicinal Chemistry 127 (2017) 434e441