Abstract
Japanese encephalitis virus (JEV) is a member of neurotropic flaviviruses transmitted by mosquito bites, causing severe central nervous system disorders. Current JEV genotype III vaccines have a low protection against genotype I isolates in the risk zone. The lead compound CW-33, ethyl 2-(3′,5′-dimethylanilino)-4-oxo-4,5-dihydrofuran-3-carboxylate, demonstrates the antiviral activity against JEV with an IC50 values of 38.5 μM for virus yield reduction (Int J Mol Sci 2016,17: E1386). This study synthesized fourteen CW-33 analogues containing a fluoro atom or one methoxy group at the C-2, C-3, or C-4 of anilino ring, and then evaluated for their antiviral activity and mechanism. Among 6 amalogues, CW-33A (ethyl 2-(2-fluoroanilino)-4-oxo- 4,5-dihydrofuran-3-carboxylate), and CW-33D (ethyl 2-(3-methoxyanilino)-4-oxo- 4,5-dihydrofuran-3-carboxylate exhibited antiviral potentials in viral cytopathic effect (CPE) inhibition. CW-33A significantly suppressed the viral protein expression, genome synthesis and intracellular JEV particle production, showing a higher inhibitory effect on JEV yield than CW-33 and CW-33D. The study demonstrated that a mono-fluoro substitution on at the C-2 anilino ring of CW-33 improved the antiviral activity JEV, revealing the structure-activity relationship for developing novel agents against JEV infection.
Highlights
Japanese encephalitis virus (JEV) is a neurotropic flavivirus that causes acute flaccid paralysis, aseptic meningitis, and encephalitis[1,2]
The analogues of CW-33 were named as CW-33A, CW-33B, CW-33C were divided into five classes according to the modification: fluoro(CW-33A, CW-33B, CW-33C) and methoxy- (CW-33D, CW-33E, CW-33F) analogues (Table 1)
Some of them showed the significant antiviral activity; the compound CW-33A had the potent activity with the IC50 value of near 1 μM. These results suggest that the derivatives with a core structure of 2-anilino-4,5-dihydrofuran-3-carboxylate significantly inhibited Japanese encephalitis virus proliferation
Summary
Japanese encephalitis virus (JEV) is a neurotropic flavivirus that causes acute flaccid paralysis, aseptic meningitis, and encephalitis[1,2]. JEV infection brings about greater than 30,000 JE cases per year included near 10,000 deaths. Recent, inactivated Nakayama and attenuated SA14-14-2 JEV vaccines have been demonstrated to reduce the protection in children from the JEV infection because JEV genotype I isolates in the risk zone were resistant to genotype III vaccine-induced neutralizing antibodies[4,5]. The compound CW-33, ethyl 2-(3′,5′-dimethylanilino)-4-oxo-4,5- dihydrofuran-3-carboxylate (Fig. 1A), exhibits antiviral activity against JEV9. The half maximal inhibitory concentration (IC50) of CW-33 to reduce the progeny virus production in vitro is greater than 10 μM, the modification of CW-33 structure to improve antiviral activity is essential. Anti-JEV activity of these CW-33 analogues was further investigated, such as cytopathic effect (CPE) inhibition www.nature.com/scientificreports/. The structure-activity relationship and antiviral mechanism(s) of bioactive CW-33 analogues were examined using the viral translation and replication assays with JEV replicon, and the viral titer assay of intracellular viral particles
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