Design, Synthesis, and Biological Evaluation of Substituted 4,6-Dihydrospiro[[1,2,3]triazolo[4,5‑b]pyridine-7,3′-indoline]-2′,5(3H)‑dione Analogues as Potent NS4B Inhibitors for the Treatment of Dengue Virus Infection
journal contributionposted on 23.08.2019, 12:10 authored by Jimin Xu, Xuping Xie, Na Ye, Jing Zou, Haiying Chen, Mark A. White, Pei-Yong Shi, Jia Zhou
A series of substituted 4,6-dihydrospiro[[1,2,3]triazolo[4,5-b]pyridine-7,3′-indoline]-2′,5(3H)-dione analogues were synthesized and evaluated as potent dengue virus inhibitors. Throughout a structure–activity relationship exploration on the amide of the indolone moiety, a wide range of substitutions were found to be well tolerated for chemical optimization at this position. Among these compounds, 15 (JMX0254) displayed the most potent and broad inhibitory activities, effective against DENV-1 to -3 with EC50 values of 0.78, 0.16, and 0.035 μM, respectively, while compounds 16, 21, 27–29, 47, and 70 exhibited relatively moderate to high activities with low micromolar to nanomolar potency against all four serotypes. The biotinylated compound 73 enriched NS4B protein from cell lysates in pull-down studies, and the findings together with the mutation investigations further validated dengue NS4B protein as the target of this class of compounds. More importantly, compound 15 exhibited good in vivo pharmacokinetic properties and efficacy in the A129 mouse model, indicating its therapeutic potential against the dengue virus infection as a drug candidate for further preclinical development.
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dengue NS 4B proteinBiological Evaluationindolone moietyEC 50 valuesmutation investigationsDengue Virus Infectioncell lysatesJMX 0254Potent NS 4B Inhibitorschemical optimizationbiotinylated compound 73nanomolar potencyDENVvivo pharmacokinetic properties0.035 μ Mdionedengue virus infectiondrug candidatedengue virus inhibitors129 mouse modelcompounds 16compound 15pyridineNS 4B protein