Biomol Ther (Seoul)  
Cinnamaldehyde Derivatives Inhibited Coxsackievirus B3-Induced Viral Myocarditis
Xiao-Qiang Li1,†, Xiao-Xiao Liu1,†, Xue-Ying Wang1, Yan-Hua Xie2, Qian Yang2, Xin-Xin Liu2, Yuan-Yuan Ding2, Wei Cao2,* and Si-Wang Wang 2,*
Departments of 1Pharmacology, 2Natural Medicine and Institute of Materia Medica, School of Pharmacy, Fourth Military Medical University, Xi’an 710032, China
E-mail: caowei@fmmu.edu.cn (Cao W), wangsiw@fmmu.edu.cn (Wang SW)
Tel: +86-29-84773752 (Cao W), +86-29-84772519 (Wang SW)
Fax: +86-29-84773752 (Cao W), +86-29-83224790 (Wang SW)
The first two authors contributed equally to this work.
Received: March 28, 2016; Revised: May 15, 2016; Accepted: June 13, 2016; Published online: October 17, 2016.
© The Korean Society of Applied Pharmacology. All rights reserved.

Abstract
The chemical property of cinnamaldehyde is unstable in vivo, although early experiments have shown its obvious therapeutic effects on viral myocarditis (VMC). To overcome this problem, we used cinnamaldehyde as a leading compound to synthesize derivatives. Five derivatives of cinnamaldehyde were synthesized: 4-methylcinnamaldehyde (1), 4-chlorocinnamaldehyde (2), 4-methoxycinnamaldehyde (3), α-bromo-4-methylcinnamaldehyde (4), and α-bromo-4-chlorocinnamaldehyde (5). Neonatal rat cardiomyocytes and HeLa cells infected by coxsackievirus B3 (CVB3) were used to evaluate their antiviral and cytotoxic effects. In vivo BALB/c mice were infected with CVB3 for establishing VMC models. Among the derivatives, compound 4 and 5 inhibited the CVB3 in HeLa cells with the half-maximal inhibitory concentrations values of 11.38 ± 2.22 μM and 2.12 ± 0.37 μM, respectively. The 50% toxic concentrations of compound 4 and 5-treated cells were 39-fold and 87-fold higher than in the cinnamaldehyde group. Compound 4 and 5 effectively reduced the viral titers and cardiac pathological changes in a dose-dependent manner. In addition, compound 4 and 5 significantly inhibited the secretion, mRNA and protein expressions of inflammatory cytokines TNF-α, IL-1β and IL-6 in CVB3-infected cardiomyocytes, indicating that brominated cinnamaldehyde not only improved the anti-vital activities for VMC, but also had potent anti-inflammatory effects in cardiomyocytes induced by CVB3.
Keywords: Anti-inflammatory, Cinnamaldehyde, Coxsackievirus B3, Myocarditis


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