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

Maksim E. Mironov, Sergey A. Borisov, Tatyana V. Rybalova, Dmitry S. Baev, Tatyana G. Tolstikova, Elvira E. Shults

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number162
JournalMolecules
Volume27
Issue number1
DOIs
Publication statusPublished - 1 Jan 2022

Keywords

  • Anti-inflammatory activity
  • Diosgenin
  • Heterocyclization
  • Multi-component synthesis
  • Pyrazole
  • Stephens–Castro reaction

OECD FOS+WOS

  • 1.06.CQ BIOCHEMISTRY & MOLECULAR BIOLOGY
  • 1.04 CHEMICAL SCIENCES

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