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