Quinolone-N-acylhydrazone hybrids as potent Zika and Chikungunya virus inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 30; no. 2; p. 126881
• Main Authors: Marra, Roberta K.F., Kümmerle, Arthur E., Guedes, Guilherme P., Barros, Caroline de S., Gomes, Rafaela S.P., Cirne-Santos, Claudio C., Paixão, Izabel Christina N.P., Neves, Amanda P.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15-01-2020
• Subjects: Animals; Antiviral activity; Arbovirus; Chikungunya; Chikungunya virus - drug effects; Chlorocebus aethiops; Humans; Quinolone-N-acylhydrazones; Quinolones - pharmacology; Quinolones - therapeutic use; Zika; Zika Virus - drug effects; Chikungunya; Arbovirus; Quinolone-N-acylhydrazones; Antiviral activity; Zika
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2019.126881

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•Quinolone-N-acylhydrazone hybrids were tested against arbovirus Zika (ZIKV) and Chikungunya (CHIKV)•The compounds exhibited excellent activities, with EC50 = 0.75–0.81 μM for ZIKV and EC50 = 1.16–2.85 μM for CHIKV.•Antiviral activity was identified by inhibition of viral RNA production in a dose-dependent manner.•The substances can be added post infection while maintaining their antiviral effect.•They can be considered excellent candidates for the development of anti-ZIKV and anti-CHIKV agents.
This work reports the synthesis of quinolone-N-acylhydrazone hybrids, namely 6-R-N'-(2-hydxoxybenzylidene)-4-oxo-1,4-dihydroquinoline-3-carbohydrazide (R = H: 5a, F: 5b, Cl: 5c and Br: 5d), which exhibited excellent activity against arbovirus Zika (ZIKV) and Chikungunya (CHIKV). In vitro screening towards ZIKV and CHIKV inhibition revealed that all substances have significant antiviral activity, most of them being more potent than standard Ribavirin (5a-d: EC50 = 0.75–0.81 μM, Ribavirin: EC50 = 3.95 μM for ZIKV and 5a-d: 1.16–2.85 μM, Ribavirin: EC50 = 2.42 μM for CHIKV). The quinolone-N-acylhydrazone hybrids were non-toxic against Vero cells, in which compounds 5c and 5d showed the best selectivities (SI = 1410 and 630 against ZIKV and CHIKV, respectively). Antiviral activity was identified by inhibition of viral RNA production in a dose-dependent manner. In the evaluation of the time of addition of the compounds, we observed that 5b and 5c remain with strong effect even in the addition for 12 h after infection. The above results indicate that quinolone-N-acylhydrazones represent a new and promising class to be further investigated as anti-ZIKV and anti-CHIKV agents.