Crystal structure, Hirshfeld surface, DFT, mol­ecular docking of 1-[(6-tert-butyl-2-oxo-2H-chromen-4-yl)meth­yl]-4,4-di­methyl­piperidine-2,6-dione and cytotoxic effects on breast cancer (MDA-MB 231), human alveolar basal epithelial (A549) cell lines

Abstract

The title compound was synthesized by S_N2 reaction of bromo­methyl coumarin with 4,4-di­methyl­piperidine-2,6-dione. Its crystal structure was determined and a Hirshfeld surface analysis was performed along with DFT, mol­ecular docking and biological activity studies.

The title compound, C₂₁H₂₅NO₄, was synthesized by S_N2 reaction of bromo­methyl coumarin with 4,4-di­methyl­piperidine-2,6-dione. The mol­ecule crystalizes in the monoclinic system with space group C2/c. The coumarin unit is almost planar with a dihedral angle between the aromatic rings of 0.81 (2)° and an r.m.s deviation of 0.042 Å. The piperidine ring adopts a chair conformation with the two methyl groups, one methyl group occupying an axial position and the other an equatorial position, exhibiting maximum stability. In the crystal, C—H⋯O inter­actions lead to the formation of head-to-head dimers with an R₂²(8)graph-set motif and R₂¹(9) and R₂²(10) ring motifs along [001] and [100]. π–π inter­actions [centroid–centroid distances = 3.885 (2) and 3.744 (2) Å] are also observed. A Hirshfeld surface analysis was carried out, with the two-dimensional fingerprint plots indicating that the major contributions to the crystal packing are from H⋯H(57%), O⋯H(29.3%) and C⋯H(8.1%) inter­actions. The energy framework calculations reveal that dispersion energy (E_dis= −267.7 kJ mol⁻¹) dominates the other energies. The mol­ecular structure was optimized by density functional theory calculations using the B3LYP/6–311+G(d,p) basis set. The HOMO and LOMO orbitals were generated to determine the energy gap, which is 4.245 eV. Mol­ecular docking studies were carried out for the title mol­ecule as ligand and a protein as receptor giving binding affinities of −9.5 kcal mol⁻¹ for PDB ID: 5HG8 and −8.2 kcal mol⁻¹ for PDB ID:6 NLV. The compound was further subjected to biological studies against human cancer cell lines, namely cryopreserved triple negative human breast adenocarcinoma cells (MDA-MB-231cells) and adenocarcinomic human alveolar basal epithelial cells (A549 cells) giving IC₅₀values of 11.57 and 9.34 µM, respectively. The cytotoxicity results showed a good safety profile against HEK293 cell lines.