TY - JOUR
T1 - Discovery of Quinoline Analogues as Potent Antivirals against Enterovirus D68 (EV-D68)
AU - Musharrafieh, Rami
AU - Zhang, Jiantao
AU - Tuohy, Peter
AU - Kitamura, Naoya
AU - Bellampalli, Shreya Sai
AU - Hu, Yanmei
AU - Khanna, Rajesh
AU - Wang, Jun
N1 - Funding Information:
This research is supported by startup funding from the University of Arizona and NIH grants AI119187 and AI144887 to J.W. R.K. is supported by National Institutes of Health Awards (1R01NS098772, 1R01DA042852, and R01AT009716). S.S.B. is supported by funding through the Spirit of Inquiry Grant from the University of Arizona Honors College.
Publisher Copyright:
© 2019 American Chemical Society.
PY - 2019/4/25
Y1 - 2019/4/25
N2 - Enterovirus D68 (EV-D68) is an atypical nonpolio enterovirus that mainly infects the respiratory system of humans, leading to moderate-to-severe respiratory diseases. In rare cases, EV-D68 can spread to the central nervous system and cause paralysis in infected patients, especially young children and immunocompromised individuals. There is currently no approved vaccine or antiviral available for the prevention and treatment of EV-D68. In this study, we aimed to improve the antiviral potency and selectivity of a previously reported EV-D68 inhibitor, dibucaine, through structure-activity relationship studies. In total, 60 compounds were synthesized and tested against EV-D68 using the viral cytopathic effect assay. Three compounds 10a, 12a, and 12c were identified to have significantly improved potency (EC50 < 1 μM) and a high selectivity index (>180) compared with dibucaine against five different strains of EV-D68 viruses. These compounds also showed potent antiviral activity in neuronal cells, such as A172 and SH-SY5Y cells, suggesting they might be further developed for the treatment of both respiratory infection as well as neuronal infection.
AB - Enterovirus D68 (EV-D68) is an atypical nonpolio enterovirus that mainly infects the respiratory system of humans, leading to moderate-to-severe respiratory diseases. In rare cases, EV-D68 can spread to the central nervous system and cause paralysis in infected patients, especially young children and immunocompromised individuals. There is currently no approved vaccine or antiviral available for the prevention and treatment of EV-D68. In this study, we aimed to improve the antiviral potency and selectivity of a previously reported EV-D68 inhibitor, dibucaine, through structure-activity relationship studies. In total, 60 compounds were synthesized and tested against EV-D68 using the viral cytopathic effect assay. Three compounds 10a, 12a, and 12c were identified to have significantly improved potency (EC50 < 1 μM) and a high selectivity index (>180) compared with dibucaine against five different strains of EV-D68 viruses. These compounds also showed potent antiviral activity in neuronal cells, such as A172 and SH-SY5Y cells, suggesting they might be further developed for the treatment of both respiratory infection as well as neuronal infection.
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U2 - 10.1021/acs.jmedchem.9b00115
DO - 10.1021/acs.jmedchem.9b00115
M3 - Article
C2 - 30912944
AN - SCOPUS:85064334138
SN - 0022-2623
VL - 62
SP - 4074
EP - 4090
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 8
ER -