Synthesis of NS2B-NS3 protease inhibitors of Dengue and Zika viruses
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Date
2024-07-23
Authors
Ζώγαλη, Βασιλική
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Abstract
Dengue and Zika viruses, members of the Flaviviridae family, are major threats to global health as 2.5 billion people worldwide are at risk of epidemic transmission. These viruses are transmitted by the mosquito Aedes aegypti whose natural habitat includes all subtropical and tropical regions, encompassing over 100 countries. Containment of Dengue or Zika became a WHO emergency and a concern for travel and tourist industry worldwide and until now there are neither appropriate antivirals nor approved vaccines that prevent infection mostly due to secondary infections caused by antibody-dependant-enhancement in cross infections with the four dengue serotypes. Drug development efforts are focused on inhibiting the non-structural proteins of these viruses particularly the protease NS2B-NS3. The NS2B-NS3 (pro) inhibitors reported to date are of limited therapeutic value largely due to their high toxicity and low permeability. In this endeavour, we decided to develop new, non-toxic, potent and cell active compounds that may lead to valuable drug candidates for flavivirus infections. Starting with an earlier WNV pro hit, we performed a scaffold hopping exercise and discovered novel N-substituted carbazole-based amidines that possessed submicromolar potency and significant cellular activity against ZIKV and DENV. We further optimised the pharmacokinetic profile of these small molecule inhibitors and performed new SAR, culminating prodrug compound SP-471P (89a) (EC50 1.10 μM, CC50 > 100 μM) that generates SP-471 (89c); one of the most potent, and cell-active allosteric, dual-mode inhibitor of the dengue protease described in the literature. In this context, an extensive scaffold morphing on the carbazole scaffold led to indolazepinones and our latest lead compound SP-1769B, arguably the most cell-efficacious against all serotypes (DENV2/3 EC50 100 nM, DENV1/4 EC50 0.95-1.25 μM) and safest (CC50 >100 μM) anti-dengue compounds reported, that also inhibits completely secondary ADE-driven infection. Encouragingly, the conserved nature of NS3 across flaviviruses presumably suggests that these compounds may evolve to broad spectrum flaviviral protease inhibitors.
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Keywords
Dengue virus carbazoles, Zika virus, Flaviviruses, Infectious diseases, Development of antiviral drugs, NS3-NS2B protease, Structure-activity relationships (SAR), Carbazoles, Indoles, Amidines, Amidoximes, Auzuki reaction, Prodrugs