Cell-active carbazole derivatives as inhibitors of the zika virus protease.

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Rassias, Gerasimos
Zogali, Vasiliki
Swarbrick, Crystall MD
Chan, Kitti Wing Ki
Chan, Shu Ann
Gwee, Chin Piaw
Wang, Sai
Kaplanai, Entzy
Canko, Aleksander
Kiousis, Dimitrios
Lescar, Julien
Luo, Dahai
Matsoukas, Minos-Timotheos
Vasudevan, Subhash G
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2019
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http://creativecommons.org/licenses/by-nc-nd/4.0/
Abstract

Zika virus (ZIKV) infection recently resulted in an international health emergency the Americas in and despite its high profile there is currently no approved treatment for ZIKV infection with millions of people being at risk. ZIKV is a member of Flaviviridae family which includes prominent members such as dengue virus (DENV) and West Nile virus (WNV). One of the best validated targets for developing anti-flaviviral treatment for DENV and WNV infection is the NS2B/NS3 protease. However the inhibitors reported to date have shown limited promise for further clinical development largely due to poor cellular activity. Prompted by the conserved nature of the viral NS2B/NS3 protease across flaviviruses, we envisaged that small molecule inhibitors of the ZIKVpro may be developed by applying rational design on previously reported scaffolds with demonstrated activity against other flaviviral proteases. Starting with an earlier WNVpro hit we performed a scaffold hopping exercise and discovered that certain carbazole derivatives bearing amidine groups possessed submicromolar potency and significant cellular activity against ZIKV. We successfully addressed various issues with the synthesis of novel N-substituted carbazole-based amidines thus permitting a targeted SAR campaign. The in vitro biochemical and cell-based inhibitory profiles exhibited by the lead molecule described in this work (ZIKVpro IC50 0.52 μM, EC50 1.25 μM), is among the best reported to date. Furthermore, these molecules possess capacity for further optimization of pharmacokinetics and may evolve to broad spectrum flaviviral protease inhibitors.

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European Journal of Medicinal Chemistry
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180
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© 2019 Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence (http://creativecommons.org/licenses/by-nc-nd/4.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, providing that the work is properly cited.
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Subject
Medicinal and biomolecular chemistry
Organic chemistry
Pharmacology and pharmaceutical sciences
Amidines
Carbazoles
Flavivirus
Inhibitors
Protease
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Citation
Rassias, G; Zogali, V; Swarbrick, CMD; Ki Chan, KW; Chan, SA; Gwee, CP; Wang, S; Kaplanai, E; Canko, A; Kiousis, D; Lescar, J; Luo, D; Matsoukas, M-T; Vasudevan, SG, Cell-active carbazole derivatives as inhibitors of the zika virus protease., European Journal of Medicinal Chemistry, 2019, 180, pp. 536-545
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