Synthesis, spectroscopic, SC-XRD, DFT, RAHBs, RDG, molecular docking and in vitro anticancer evaluation of ethyl 1,2,5,6-tetrahydro-4-hydroxy-2,6-diphenylpyridine-3-carboxylate

A desmotropic compound of ethyl 1,2,5,6-tetrahydro-4-hydroxy-2,6-diphenylpyridine-3-carboxylate (THDC) has been synthesized by one pot multicomponent reaction of benzaldehyde, ammonium acetate and ethylacetoacetate. The compound was thoroughly characterized by FT-IR, as well as 1D and 2D NMR spectroscopic methods. The study indicates that the expected molecular structure exists in pure enol form rather than its corresponding keto form (Ethyl 4-oxo-2,6-diphenyl-4-piperidine-3-carboxylate, EODPC), a finding further validated by SC-XRD technique. Additionally, this finding shows the strong S(6) intramolecular hydrogen bond, whose donor-acceptor (O1 center dot center dot center dot O2) bond distance was found to be 2.81 A. The spectroscopic and SC-XRD analyses suggest that the piperidine ring adopts a half boat conformation with axial and equatorial orientation of two phenyl rings. An extensive analysis of intramolecular hydrogen bonding was conducted using the non-covalent interaction-radiant density gradient (NCI-RDG) plot. Similarly, the intermolecular contacts are determined quantitatively with the aid of three-dimensional Hirshfeld surfaces and a two-dimensional fingerprint plots. In addition, DFT studies, energy framework analysis and bioavailability of the THDC compound were examined to understand the energy, electronic and drug like properties. The in silico molecular docking study was also performed for desmotropic compounds (EODPC and THDC) with endothelial growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGFR2) kinase enzymes. Finally, cytotoxic and apoptotic effects were studied for these compounds using A549 Lung cancer cells.