Use of 3-(trifluoromethyl)-1H-pyrazolo-[3,4-b]pyridine as a versatile building block

Schirok, Hartmut; Griebenow, Nils; Fürstner, Chantal; Dilmaç, Alicia M.

doi:10.1016/j.tet.2015.06.050

Cited by 10 publications

(4 citation statements)

References 33 publications

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“…However, preparation of the parent compound 87 proved difficult because it was unstable under our standard conditions used to hydrolyze the bis-sulphonamides formed in the reaction (1:1 methanol:aqueous NaOH, see Chemistry section, Scheme ), undergoing significant hydrolysis at room temperature to generate the methoxy ester 93 as shown in Scheme . This reactivity of some −CF3 groups on heterocyclic rings has been previously described. − Subsequent preparation of 87 via milder methods was successful, but unfortunately the compound was inactive in the MIC assay (Table ), possibly due to similar chemical stability issues under the assay conditions.…”

Section: Resultsmentioning

confidence: 52%

Exploring the SAR of the β-Ketoacyl-ACP Synthase Inhibitor GSK3011724A and Optimization around a Genotoxic Metabolite

et al. 2020

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In the course of optimizing a novel indazole sulfonamide series that inhibits β-ketoacyl-ACP synthase (KasA) of Mycobacterium tuberculosis, a mutagenic aniline metabolite was identified. Further lead optimization efforts were therefore dedicated to eliminating this critical liability by removing the embedded aniline moiety or modifying its steric or electronic environment. While the narrow SAR space against the target ultimately rendered this goal unsuccessful, key structural knowledge around the binding site of this underexplored target for TB was generated to inform future discovery efforts.

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Section: Resultsmentioning

confidence: 52%

Exploring the SAR of the β-Ketoacyl-ACP Synthase Inhibitor GSK3011724A and Optimization around a Genotoxic Metabolite

et al. 2020

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“…The 3-aminoindazole 1h (Lefebvre et al, 2010 ) was reacted with 4-(chlorosulfonyl)phenyl pivalate 2 in dry 1,4-dioxane/DMF, Et 3 N at 50 °C to obtain the intermediate 3h , which was further elaborated by treatment with m-toluoyl chloride in anhydrous CH 2 Cl 2 and Et 3 N to obtain the final compound 4 , containing a benzamido moiety at position 3. Lastly, synthesis of the 7-azaindoles 3i , j and 7-azaindazoles 3k , l was performed starting from precursors 1i,j and 1-k,l ( 1i : Bahekar et al, 2007 ; 1j : Crocetti et al, 2018 ; 1k,l : Schirok et al, 2015 ), respectively, under the same conditions described for compounds 3d-f .…”

Section: Resultsmentioning

confidence: 99%

“…Compounds 3i-l and 4 were obtained starting from intermediates 1i-l (1i: Bahekar et al, 2007 ; 1j: Crocetti et al, 2018 ; 1k,l: Schirok et al, 2015 ) and 3h , respectively, following the same procedure described for 3d-f and using the appropriate sulfonyl chloride 2 (Hwang et al, 2015 ) (for 3i-l ) or m-toluoyl chloride (for 4 ) as reagents. After evaporation of organic solvent, ice-cold water was added (20 mL).…”

Section: Methodsmentioning

confidence: 99%

Novel Sulfonamide Analogs of Sivelestat as Potent Human Neutrophil Elastase Inhibitors

et al. 2020

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Human neutrophil elastase (HNE) is involved in a number of essential physiological processes and has been identified as a potential therapeutic target for treating acute and chronic lung injury. Nevertheless, only one drug, Sivelestat, has been approved for clinical use and just in Japan and the Republic of Korea. Thus, there is an urgent need for the development of low-molecular-weight synthetic HNE inhibitors, and we have developed a wide variety of HNE inhibitors with various chemical scaffolds. We hypothesized that substitution of the active fragment of Sivelestat into these HNE inhibitor scaffolds could modulate their inhibitory activity, potentially resulting in higher efficacy and/or improved chemical stability. Here, we report the synthesis, biological evaluation, and molecular modeling studies of novel compounds substituted with the 4-(sulfamoyl)phenyl pivalate fragment necessary for Sivelestat activity. Many of these compounds were potent HNE inhibitors with activity in the nanomolar range (IC 50 = 19-30 nM for compounds 3a, 3b, 3f, 3g, and 9a), confirming that the 4-(sulfamoyl)phenyl pivalate fragment could substitute for the N-CO group at position 1 and offer a different point of attack for Ser195. Results of molecular docking of the these pivaloyl-containing compounds into the HNE binding site supported the mechanism of inhibitory activity involving a nucleophilic attack of Ser195 from the catalytic triad onto the pivaloyl carbonyl group. Furthermore, some compounds (e.g., 3a and 3f) had a relatively good stability in aqueous buffer (t 1/2 > 9 h). Thus, this novel approach led to the identification of a number of potent HNE inhibitors that could be used as leads for the further development of new therapeutics.

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“…Nonetheless, an underwhelming effort has been devoted to the efficient synthesis of the pyrazolopyridine derivatives. To the best of our knowledge, the construction of the pyrazolopyridine skeleton usually started from pyrazoles directly under heating or microwave conditions, ,, and a few reports were involved in reacting the pyridine ring with hydrazine to get the pyrazolopyridines. ,,, However, existing substituted pyrazoles and pyridines were limited from commercial suppliers, and most of them have to be synthesized by chemists themselves. The resulting lengthy syntheses increases the number of laboratory operations, the quantities of agents and solvents used, regardless of the harsh reaction conditions in some cases.…”

Section: Introductionmentioning

confidence: 99%

“On-Water” Facile Synthesis of Novel Pyrazolo[3,4-b]pyridinones Possessing Anti-influenza Virus Activity

Zeng

Yang

et al. 2017

ACS Comb. Sci.

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A facile and versatile "on-water" protocol for the synthesis of pyrazolo[3,4-b]pyridinones was developed by the unprecedented construction of two rings and five new bonds in one-pot. It was proved that water was an important promoter of the reaction and PEG2000 was found to improve the reaction in terms of yield. 32 Derivatives were newly synthesized and most of them were prepared in an hour. The scope and limitation indicated that electron withdrawing groups substituted on synthons, substituted benzoyl acetonitriles or aryl aldehydes, were helpful to construct the pyrazolo[3,4-b]pyridinones. The reaction media PEG2000/HO was successfully recycled and reused at least 5 times without any obvious decrease in yield. The anti-influenza activities of the derivatives were evaluated and the screening results highlighted two derivatives, which exhibited strong inhibitory activity against H5N1 pseudovirus. These positive bioassay results implied that the library of potential anti-influenza virus agent candidates could be rapidly prepared in an eco-friendly manner, and provided a new insight into drug discovery for medicinal chemists.

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Use of 3-(trifluoromethyl)-1H-pyrazolo-[3,4-b]pyridine as a versatile building block

Cited by 10 publications

References 33 publications

Exploring the SAR of the β-Ketoacyl-ACP Synthase Inhibitor GSK3011724A and Optimization around a Genotoxic Metabolite

Exploring the SAR of the β-Ketoacyl-ACP Synthase Inhibitor GSK3011724A and Optimization around a Genotoxic Metabolite

Novel Sulfonamide Analogs of Sivelestat as Potent Human Neutrophil Elastase Inhibitors

“On-Water” Facile Synthesis of Novel Pyrazolo[3,4-b]pyridinones Possessing Anti-influenza Virus Activity

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