Synthesis and Spectroscopic Analysis of Piperine- and Piperlongumine-Inspired Natural Product Scaffolds and Their Molecular Docking with IL-1β and NF-κB Proteins

Abstract

Inspired by the remarkable bioactivities exhibited by the natural products, piperine and piperlongumine, we synthesised eight natural product-inspired analogues to further investigate their structures. For the first time, we confirmed the structure of the key cyclised dihydropyrazolecarbothioamide piperine analogues including the use of two-dimensional (2D) 15N-based spectroscopy nuclear magnetic resonance (NMR) spectroscopy. Prior investigations demonstrated promising results from these scaffolds for the inhibition of inflammatory response via downregulation of the IL-1β and NF-κB pathway. However, the molecular interaction of these molecules with their protein targets remains unknown. Ab initio calculations revealed the electronic density function map of the molecules, showing the effects of structural modification in the electronic structure. Finally, molecular interactions between the synthesized molecules and the proteins IL-1β and NF-κB were achieved. Docking results showed that all the analogues interact in the DNA binding site of NF-κB with higher affinity compared to the natural products and, with the exception of 9a and 9b, have higher affinity than the natural products for the binding site of IL-1β. Specificity for the molecular recognition of 3a, 3c and 9b with IL-1β through cation–π interactions was determined. These results revealed 3a, 3c, 4a, 4c and 10 as the most promising molecules to be evaluated as IL-1β and NF-κB inhibitors.

Synthesis and Bioactivities of Novel Piperonylic Acid Derivatives Containing a Sulfonic Acid Ester Moiety

“…The synthetic route for the final compounds 4a – 4x were depicted in Scheme 1 . Intermediates 1–2 were synthesized according to a previously reported method ( Dam and Madsen, 2009 ; Zazeri et al, 2020 ). Intermediate 3 was prepared according to literature method ( Joseph et al, 2019 ).…”

A novel exchange method to access sulfated molecules

“…1 H, 13 C and 19 F NMR spectra were recorded either on a Bruker AVIII operating at 300 MHz for 1 H and fitted with a 5 mm BBFO probe or on a Bruker AVANCE NEO operating at 400 MHz for 1 H fitted with a 5 mm “smart” BBFO probe, respectively 25 . Chemical shift data are reported in parts per million (ppm, δ scale) downfield from tetramethylsilane (TMS: δ 0.0) and referenced internally to the residual proton in the solvent 26 .…”

The Cytokine IL-1β and Piperine Complex Surveyed by Experimental and Computational Molecular Biophysics

“…AutoDockTools [ 11 ] software of the MGL program Tools 1.5.4 was used to prepare the proteins by adding polar hydrogen atoms and Gasteiger charges. Blind docking was performed to explore the whole IL-1β protein following the previously described procedures [ 12 ]. The maps were generated by AutoGrid 4.2 program with a spacing of 0.4583 Å, dimension of 126 × 126 × 108 points and grid center coordinates of 41.028, −0.369 and 12.346 for x, y and z coordinates, respectively.…”