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

• Published in: European journal of medicinal chemistry 2024-03, Vol.268, p.116213-116213, Article 116213
• Main Authors: Zogali, Vasiliki, Kiousis, Dimitrios, Voutyra, Stefania, Kalyva, Georgia, Abdul Mahid, Maharah Binte, Bist, Pradeep, Ki Chan, Kitti Wing, Vasudevan, Subhash G., Rassias, Gerasimos
• Format: Article
• Language: English
• Subjects: Amidoximes; Antivirals; Dengue; Indoles; Prodrugs; SAR; Zika
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116213

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, EC50 1.1 μM, CC50 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 EC50 100 nM, DENV1/4 EC50 0.95–1.25 μM) and safest (CC50 > 100 μM) anti-dengue compounds in the literature that also completely inhibits a secondary ADE-driven infection. [Display omitted] •Scaffold morphing on our previous hit led to a novel, pan-serotype, potent and safe DENV inhibitor.•Compounds were cross-examined in plaque reduction and dose-dependent inhibition cell assays.•Exemplified the importance of the relative spatial arrangement of three domain pharmacophore.•The synthesis of all compounds was optimised and performed to gram-scale reactions.