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
Posted on 2019-08-23 - 12:10
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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Xu, Jimin; Xie, Xuping; Ye, Na; Zou, Jing; Chen, Haiying; White, Mark A.; et al. (2019). 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. ACS Publications. Collection. https://doi.org/10.1021/acs.jmedchem.9b00698
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AUTHORS (8)
JX
Jimin Xu
XX
Xuping Xie
NY
Na Ye
JZ
Jing Zou
HC
Haiying Chen
MW
Mark A. White
PS
Pei-Yong Shi
JZ
Jia Zhou
KEYWORDS
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