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Chemical Structure| 2049109-24-0 Chemical Structure| 2049109-24-0

Structure of 2049109-24-0

Chemical Structure| 2049109-24-0

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Product Citations

Product Citations

Werman, Joshua M. ; Chen, Yu-Ching ; Yuan, Tianao ; Yang, Xinxin ; Sampson, Nicole S. ;

Abstract: By illuminating key 6-azasteroid-protein interactions in both Mycobacterium tuberculosis (Mtb) and the closely related model organism Mycobacterium marinum (Mm), we sought to improve the antimycobacterial potency of 6-azasteroids and further our understanding of the mechanisms responsible for their potentiation of the antituberculosis drug bedaquiline. We selected a newly developed 6-azasteroid analog and an analog reported previously (ACS Infect. Dis.2019, 5 (7), 1239-1251) to study their phenotypic effects on Mtb and Mm, both alone and in combination with bedaquiline. The 6-azasteroid analog, 17β-[N-(4-trifluoromethoxy-diphenylmethyl)carbamoyl]-6-propyl-azaandrostan-3-one, robustly potentiated bedaquiline-mediated antimycobacterial activity, with a nearly 8-fold reduction in Mm bedaquiline minimal inhibitory concentration (85 nM alone vs. 11 nM with 20 μM 6-azasteroid). This analog displayed minimal inhibitory activity against recombinant mycobacterial 3β-hydroxysteroid dehydrogenase, a previously identified target of several 6-azasteroids. Dose-dependent potentiation of bedaquiline by this analog reduced mycobacterial intracellular ATP levels and impeded the ability of Mtb to neutralize exogenous oxidative stress in culture. We developed two 6-azasteroid photoaffinity probes to investigate azasteroid-protein interactions in Mm whole cells. Using bottom-up mass spectrometric profiling of the cross-linked proteins, we identified eight potential Mm/Mtb protein targets for 6-azasteroids. The nature of these potential targets indicates that proteins related to oxidative stress resistance play a key role in the BDQ-potentiating activity of azasteroids and highlights the potential impact of inhibition of these targets on the generation of drug sensitivity.

Keywords: photoaffinity label ; click chemistry ; synergy ; potentiator ; oxidative stress ; inhibitor

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Product Details of [ 2049109-24-0 ]

CAS No. :2049109-24-0
Formula : C7H8N2O2
M.W : 152.15
SMILES Code : C#CCCC1(N=N1)CC(O)=O
MDL No. :MFCD31922730
InChI Key :TWWYBNRREWIKHQ-UHFFFAOYSA-N
Pubchem ID :137346505

Safety of [ 2049109-24-0 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H226-H314
Precautionary Statements:P210-P240-P242-P243-P264-P271-P280-P301+P330+P331-P303+P361+P353-P304+P340-P305+P351+P338-P310-P363-P370+P378-P403+P233-P501
Class:3(8)
UN#:2924
Packing Group:
 

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[ 2049109-24-0 ]

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