Discovery of a Novel Privileged Acrylamide Scaffold as a Potent HSP90 Inhibitor: Synthesis, Crystal Structure, DFT Investigation, Molecular Docking, Dynamics Simulations, and ADMET Properties

Abstract

A new compound featuring a privileged acrylamide scaffold, (E)‐N‐(3‐cyanothiophen‐2‐yl)‐3‐(2‐nitrophenyl)‐N‐((E)‐3‐(2‐nitrophenyl)acryloyl)acrylamide (CNNA‐acrylamide), was synthesized via the reaction of trans‐2‐nitrocinnamoyl chloride with 2‐aminothiophen‐3‐carbonitrile in the presence of triethylamine. The structure of the compound was elucidated using FT‐IR, 1 H NMR, 1 3 C NMR, elemental analysis, and single‐crystal x‐ray diffraction (SC‐XRD). Crystallographic analysis revealed that non‐covalent interactions, particularly C─H⋯O contacts, contribute to the stabilization of the crystal packing. The computational investigation comprised density functional theory (DFT) calculations, molecular docking, molecular dynamics (MD) simulations, and binding free energy analyses. DFT studies included geometry optimization, frequency analysis, molecular electrostatic potential (MEP) mapping, and frontier molecular orbital (FMO) analysis. The inhibitory potential of CNNA‐acrylamide toward heat shock protein 90 (HSP90) was evaluated through molecular docking, followed by MD simulations and binding free energy calculations, and the results were compared with those of the reference inhibitors Geldanamycin and BIIB021. The results suggest that CNNA‐acrylamide exhibits binding behavior toward HSP90 comparable to that of the reference compounds.Finally, drug‐likeness and ADMET analyses were performed to assess the pharmacokinetic profile of the compound. The findings provide a basis for the rational design and further development of potential HSP90 inhibitors.