Revisiting Biginelli-like reactions: solvent effects, mechanisms, biological applications and correction of several literature reports.
Pedro S BeckArthur G LeitãoYasmin B SantanaJosé R CorreaCarime V S RodriguesDaniel F S MachadoGuilherme D R MatosLuciana M RamosClaudia C GattoSarah C C OliveiraCarlos Kleber Z AndradeBrenno A D NetoPublished in: Organic & biomolecular chemistry (2024)
This study critically reevaluates reported Biginelli-like reactions using a Kamlet-Abboud-Taft-based solvent effect model. Surprisingly, structural misassignments were discovered in certain multicomponent reactions, leading to the identification of pseudo three-component derivatives instead of the expected MCR adducts. Attempts to replicate literature conditions failed, prompting reconsideration of the described MCRs and proposed mechanisms. Electrospray ionization (tandem) mass spectrometry, NMR, melting points, elemental analyses and single-crystal X-ray analysis exposed inaccuracies in reported MCRs and allowed for the proposition of a complete catalytic cycle. Biological investigations using both pure and "contaminated" derivatives revealed distinctive features in assessed bioassays. A new cellular action mechanism was unveiled for a one obtained pseudo three-component adduct, suggesting similarity with the known dihydropyrimidinone Monastrol as Eg5 inhibitors, disrupting mitosis by forming monoastral mitotic spindles. Docking studies and RMSD analyses supported this hypothesis. The findings described herein underscore the necessity for a critical reexamination and potential corrections of structural assignments in several reports. This work emphasizes the significance of rigorous characterization and critical evaluation in synthetic chemistry, urging a careful reassessment of reported synthesis and biological activities associated with these compounds.
Keyphrases
- high resolution
- tandem mass spectrometry
- ultra high performance liquid chromatography
- systematic review
- high performance liquid chromatography
- liquid chromatography
- gas chromatography
- simultaneous determination
- escherichia coli
- mass spectrometry
- ionic liquid
- adverse drug
- solid phase extraction
- heavy metals
- magnetic resonance
- cell cycle
- molecular dynamics simulations
- molecular dynamics
- multidrug resistant
- drinking water
- single cell
- protein protein
- computed tomography
- high resolution mass spectrometry
- klebsiella pneumoniae
- ms ms
- human health
- magnetic resonance imaging
- bioinformatics analysis