Abstract:
: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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Xu J,Xie X,Ye N,Zou J,Chen H,White MA,Shi PY,Zhou Jdoi
10.1021/acs.jmedchem.9b00698subject
Has Abstractpub_date
2019-09-12 00:00:00pages
7941-7960issue
17eissn
0022-2623issn
1520-4804journal_volume
62pub_type
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