Carbazole to indolazepinone scaffold morphing leads to potent cell-active dengue antivirals.

According to WHO, dengue virus is classed among major threats for future pandemics and remains at large an unmet medical need as there are currently no relevant antiviral drugs whereas vaccine developments have met with safety concerns, mostly due to secondary infections caused by antibody-dependant-enhancement in cross infections among the four dengue serotypes. This adds extra complexity in dengue antiviral research and has impeded the progress in this field. Following through our previous effort which born the allosteric, dual-mode inhibitor SP-471P (a carbazole derivative, EC ₅₀ 1.1 μM, CC ₅₀ 100 μM) we performed further optimisation while preserving the two arylamidoxime arms and the bromoaryl domain present in SP-471P. Examination of the relative positions of these functionalities within this three-point pharmacophore ultimately led us to an indolazepinone scaffold and our lead compound SP-1769B. SP-1769B is among the most cell-efficacious against all serotypes (DENV2/3 EC ₅₀ 100 nM, DENV1/4 EC ₅₀ 0.95-1.25 μM) and safest (CC ₅₀  > 100 μM) anti-dengue compounds in the literature that also completely inhibits a secondary ADE-driven infection.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Subhash G. Vasudevan reports financial support was provided by Duke-NUS Medical School Program in Emerging Infectious Diseases. Vasiliki Zogali reports financial support was provided by International Society for Antiviral Research. G.R. previously worked for GlaxoSmithKline, S.G.V previously worked for Novartis.
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