title: N-(2-(arylmethylimino)ethyl)-7-chloroquinolin-4-amine derivatives, synthesized by thermal and ultrasonic means, are endowed with anti-Zika virus activity.
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 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 EC50value 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.
authors.affiliation: Instituto Oswaldo Cruz, Fiocruz - Fundação Oswaldo Cruz, Rio de Janeiro, Brazil; Centro de Desenvolvimento Tecnológico em Saúde, Fiocruz - Fundação Oswaldo Cruz, Rio de Janeiro, Brazil; Instituto Nacional de Infectologia Evandro Chagas, Fiocruz - Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
authors.forename: Giselle
authors.initials: G
authors.lastname: Barbosa-Lima
authors.affiliation: Departamento de Química Orgânica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Ligia S
authors.initials: LS
authors.lastname: da Silveira Pinto
authors.affiliation: Departamento de Química Orgânica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Kaiser
authors.affiliation: Instituto de Tecnologia em Fármacos - Far-Manguinhos, Fiocruz - Fundação Oswaldo Cruz, Rio de Janeiro, Brazil; Department of Chemistry, University of Aberdeen, Old Aberdeen, Scotland, UK.
authors.forename: James L
authors.initials: JL
authors.lastname: Wardell
authors.affiliation: Instituto Oswaldo Cruz, Fiocruz - Fundação Oswaldo Cruz, Rio de Janeiro, Brazil; Centro de Desenvolvimento Tecnológico em Saúde, Fiocruz - Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
authors.forename: Caroline S
authors.initials: CS
authors.lastname: De Freitas
authors.affiliation: Instituto Oswaldo Cruz, Fiocruz - Fundação Oswaldo Cruz, Rio de Janeiro, Brazil; Centro de Desenvolvimento Tecnológico em Saúde, Fiocruz - Fundação Oswaldo Cruz, Rio de Janeiro, Brazil; Instituto Nacional de Infectologia Evandro Chagas, Fiocruz - Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
authors.forename: Yasmine R
authors.initials: YR
authors.lastname: Vieira
authors.affiliation: Instituto Oswaldo Cruz, Fiocruz - Fundação Oswaldo Cruz, Rio de Janeiro, Brazil; Centro de Desenvolvimento Tecnológico em Saúde, Fiocruz - Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
authors.forename: Andressa
authors.initials: A
authors.lastname: Marttorelli
authors.affiliation: Instituto Nacional de Infectologia Evandro Chagas, Fiocruz - Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
authors.forename: José
authors.initials: J
authors.lastname: Cerbino Neto
authors.affiliation: Instituto Oswaldo Cruz, Fiocruz - Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
authors.forename: Patrícia T
authors.initials: PT
authors.lastname: Bozza
authors.affiliation: CHEMSOL, 1 Harcourt Road, Aberdeen AB15 5 NY, Scotland, UK.
authors.forename: Solange M S V
authors.initials: SMSV
authors.lastname: Wardell
authors.affiliation: Departamento de Química Orgânica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; Instituto de Tecnologia em Fármacos - Far-Manguinhos, Fiocruz - Fundação Oswaldo Cruz, Rio de Janeiro, Brazil. Electronic address: marcos_souza@far.fiocruz.br.
authors.forename: Marcus V N
authors.initials: MVN
authors.lastname: de Souza
authors.affiliation: Instituto Oswaldo Cruz, Fiocruz - Fundação Oswaldo Cruz, Rio de Janeiro, Brazil; Centro de Desenvolvimento Tecnológico em Saúde, Fiocruz - Fundação Oswaldo Cruz, Rio de Janeiro, Brazil; Instituto Nacional de Infectologia Evandro Chagas, Fiocruz - Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
authors.forename: Thiago M L
authors.initials: TML
authors.lastname: Souza
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D002738:Chloroquine / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D013696:Temperature; D000069453:Ultrasonic Waves; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects; D000071244:Zika Virus / Q000187:drug effects* / Q000502:physiology
chemical_list: D000998:Antiviral Agents; D002738:Chloroquine
keywords: Quinoline derivatives; Sonochemical method; Zika virus