Synthesis of anti-inflammatory spirostene-pyrazole conjugates by a consecutive multicomponent reaction of diosgenin with oxalyl chloride, arylalkynes and hydrazines or hydrazones

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Synthesis of anti-inflammatory spirostene-pyrazole conjugates by a consecutive multicomponent reaction of diosgenin with oxalyl chloride, arylalkynes and hydrazines or hydrazones. / Mironov, Maksim E.; Borisov, Sergey A.; Rybalova, Tatyana V. et al.

In: Molecules, Vol. 27, No. 1, 162, 01.01.2022.

Research output: Contribution to journal › Article › peer-review

BibTeX

@article{c18b8ecb036f4b02a325106bc219d33d,

title = "Synthesis of anti-inflammatory spirostene-pyrazole conjugates by a consecutive multicomponent reaction of diosgenin with oxalyl chloride, arylalkynes and hydrazines or hydrazones",

abstract = "Steroid sapogenin diosgenin is of significant interest due to its biological activity and synthetic application. A consecutive one-pot reaction of diosgenin, oxalyl chloride, arylacetylenes, and phenylhydrazine give rise to steroidal 1,3,5-trisubstituted pyrazoles (isolated yield 46–60%) when the Stephens–Castro reaction and heterocyclization steps were carried out by heating in benzene. When the cyclization step of alkyndione with phenylhydrazine was performed in 2-methoxyethanol at room temperature, steroidal α,β-alkynyl (E)-and (Z)-hydrazones were isolated along with 1,3,5-trisubstituted pyrazole and the isomeric 2,3,5-trisubstituted pyrazole. The consecutive reaction of diosgenin, oxalyl chloride, phenylacetylene and benzoic acid hydrazides efficiently forms steroidal 1-benzoyl-5-hydroxy-3-phenylpyrazolines. The structure of new compounds was unambiguously corroborated by comprehensive NMR spectroscopy, mass-spectrometry, and X-ray structure analyses. Performing the heterocyclization step of ynedione with hydrazine monohydrate in 2-methoxyethanol allowed the synthesis of 5-phenyl substituted steroidal pyrazole, which was found to exhibit high anti-inflammatory activity, comparable to that of diclofenac sodium, a commercial pain reliever. It was shown by molecular docking that the new derivatives are incorporated into the binding site of the protein Keap1 Kelch-domain by their alkynylhydrazone or pyrazole substituent with the formation of more non-covalent bonds and have higher affinity than the initial spirostene core.",

keywords = "Anti-inflammatory activity, Diosgenin, Heterocyclization, Multi-component synthesis, Pyrazole, Stephens–Castro reaction",

author = "Mironov, {Maksim E.} and Borisov, {Sergey A.} and Rybalova, {Tatyana V.} and Baev, {Dmitry S.} and Tolstikova, {Tatyana G.} and Shults, {Elvira E.}",

note = "Funding Information: This work was financially supported by the Russian Science Foundation (grant number 18-13-00361). Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2022",

month = jan,

day = "1",

doi = "10.3390/molecules27010162",

language = "English",

volume = "27",

journal = "Molecules",

issn = "1420-3049",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "1",

}

RIS

TY - JOUR

T1 - Synthesis of anti-inflammatory spirostene-pyrazole conjugates by a consecutive multicomponent reaction of diosgenin with oxalyl chloride, arylalkynes and hydrazines or hydrazones

AU - Mironov, Maksim E.

AU - Borisov, Sergey A.

AU - Rybalova, Tatyana V.

AU - Baev, Dmitry S.

AU - Tolstikova, Tatyana G.

AU - Shults, Elvira E.

N1 - Funding Information: This work was financially supported by the Russian Science Foundation (grant number 18-13-00361). Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2022/1/1

Y1 - 2022/1/1

N2 - Steroid sapogenin diosgenin is of significant interest due to its biological activity and synthetic application. A consecutive one-pot reaction of diosgenin, oxalyl chloride, arylacetylenes, and phenylhydrazine give rise to steroidal 1,3,5-trisubstituted pyrazoles (isolated yield 46–60%) when the Stephens–Castro reaction and heterocyclization steps were carried out by heating in benzene. When the cyclization step of alkyndione with phenylhydrazine was performed in 2-methoxyethanol at room temperature, steroidal α,β-alkynyl (E)-and (Z)-hydrazones were isolated along with 1,3,5-trisubstituted pyrazole and the isomeric 2,3,5-trisubstituted pyrazole. The consecutive reaction of diosgenin, oxalyl chloride, phenylacetylene and benzoic acid hydrazides efficiently forms steroidal 1-benzoyl-5-hydroxy-3-phenylpyrazolines. The structure of new compounds was unambiguously corroborated by comprehensive NMR spectroscopy, mass-spectrometry, and X-ray structure analyses. Performing the heterocyclization step of ynedione with hydrazine monohydrate in 2-methoxyethanol allowed the synthesis of 5-phenyl substituted steroidal pyrazole, which was found to exhibit high anti-inflammatory activity, comparable to that of diclofenac sodium, a commercial pain reliever. It was shown by molecular docking that the new derivatives are incorporated into the binding site of the protein Keap1 Kelch-domain by their alkynylhydrazone or pyrazole substituent with the formation of more non-covalent bonds and have higher affinity than the initial spirostene core.

AB - Steroid sapogenin diosgenin is of significant interest due to its biological activity and synthetic application. A consecutive one-pot reaction of diosgenin, oxalyl chloride, arylacetylenes, and phenylhydrazine give rise to steroidal 1,3,5-trisubstituted pyrazoles (isolated yield 46–60%) when the Stephens–Castro reaction and heterocyclization steps were carried out by heating in benzene. When the cyclization step of alkyndione with phenylhydrazine was performed in 2-methoxyethanol at room temperature, steroidal α,β-alkynyl (E)-and (Z)-hydrazones were isolated along with 1,3,5-trisubstituted pyrazole and the isomeric 2,3,5-trisubstituted pyrazole. The consecutive reaction of diosgenin, oxalyl chloride, phenylacetylene and benzoic acid hydrazides efficiently forms steroidal 1-benzoyl-5-hydroxy-3-phenylpyrazolines. The structure of new compounds was unambiguously corroborated by comprehensive NMR spectroscopy, mass-spectrometry, and X-ray structure analyses. Performing the heterocyclization step of ynedione with hydrazine monohydrate in 2-methoxyethanol allowed the synthesis of 5-phenyl substituted steroidal pyrazole, which was found to exhibit high anti-inflammatory activity, comparable to that of diclofenac sodium, a commercial pain reliever. It was shown by molecular docking that the new derivatives are incorporated into the binding site of the protein Keap1 Kelch-domain by their alkynylhydrazone or pyrazole substituent with the formation of more non-covalent bonds and have higher affinity than the initial spirostene core.

KW - Anti-inflammatory activity

KW - Diosgenin

KW - Heterocyclization

KW - Multi-component synthesis

KW - Pyrazole

KW - Stephens–Castro reaction

UR - http://www.scopus.com/inward/record.url?scp=85122034125&partnerID=8YFLogxK

U2 - 10.3390/molecules27010162

DO - 10.3390/molecules27010162

M3 - Article

C2 - 35011399

AN - SCOPUS:85122034125

VL - 27

JO - Molecules

JF - Molecules

SN - 1420-3049

IS - 1

M1 - 162

ER -

ID: 35228390