Zika virus (ZIKV) infection recently resulted in an international health emergency in the Americas in 2015-16 and despite its high profile there is still 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 improved 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 (ZIKVpro IC 50 0.5-0.8 µM) and cell-based (EC 50 1-2 µM) inhibitory profiles exhibited by the novel lead molecules described in this work, are 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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