Quinolone-N-acylhydrazone hybrids as potent Zika and Chikungunya virus inhibitors |
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| Affiliation: | 1. Department of Medicine, Division of Infectious Diseases and Geographic Medicine, and Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA;2. Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA;3. Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA;1. Department of Chemistry, Fudan University, Shanghai 200433, People’s Republic of China;2. Institute of Biomedical Science, Fudan University, Shanghai 200433, People’s Republic of China;3. Rega Institute for Medical Research, Katholieke Universiteit Leuven, 10 Minderbroedersstraat, B-3000 Leuven, Belgium;1. Department of Pharmacy, Faculty of Science, National University of Singapore, Block S4A, Level 3, 18 Science Drive 4, 117543, Singapore;2. Laboratory of Molecular RNA Virology and Antiviral Strategies, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, 117545, Singapore;3. Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-University Munich, 81377, Munich, Germany;4. School of Pharmacy, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom;5. Infectious Diseases Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Drive, 117597, Singapore;1. ICMR-National Institute of Virology, 20-A, Dr. Ambedkar Road, Pune, 411001, Maharashtra, India;2. Department of Applied Biology, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad, 500 007, India;1. Instituto Oswaldo Cruz, Fiocruz - Fundação Oswaldo Cruz, Rio de Janeiro, Brazil;2. Centro de Desenvolvimento Tecnológico em Saúde, Fiocruz - Fundação Oswaldo Cruz, Rio de Janeiro, Brazil;3. Instituto Nacional de Infectologia Evandro Chagas, Fiocruz - Fundação Oswaldo Cruz, Rio de Janeiro, Brazil;4. Instituto de Tecnologia em Fármacos - Far-Manguinhos, Fiocruz - Fundação Oswaldo Cruz, Rio de Janeiro, Brazil;5. Departamento de Química Orgânica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil |
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| Abstract: | 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. |
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| Keywords: | Quinolone-N-acylhydrazones Arbovirus Zika Chikungunya Antiviral activity |
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