An analysis of structural, spectroscopic, quantum chemical and in silico studies of ethyl 3-[(pyridin-2-yl)amino]propanoate: A potential thrombin inhibitor

Abstract

Abstract In the present investigation, we report an analysis of the structural, spectroscopic characterization, reactivity parameters, topological studies, and molecular docking studies of the synthesized ethyl 3-[(pyridin-2-yl)amino]propanoate (abbreviated to EPYAPP), C10H14N2O2. The molecular and crystal structure was determined by using the single-crystal X-ray diffraction technique. The whole molecule is planar with r.m.s.d. of all the non-hydrogen atoms being 0.041(2) A. Further, the dihedral angle between the planes of the aromatic ring and the side chain is 1.6(1)o. The crystal structure features a pair of N-H…N hydrogen-bonded dimers connected via two C-H...π (π electrons of the aromatic ring) interactions to form a two-dimensional zig-zag sheet propagating parallel to the bc plane. The qualitative and quantitative estimation of close contacts in the solid phase of the title compound was performed through the 3D-Hirshfeld surface analysis and 2D-finger print plots. The quantum chemical calculations of the EPYAPP compound were performed at DFT/B3LYP/6-311++G(d,p) method at the ground state in the gas phase. The detailed investigation of each vibrational wave number was carried out by using the VEDA4 package, and theoretical results showed an excellent mutual agreement with the experimental spectral data. The HOMO-LUMO orbital energy calculations, chemical reactivity descriptors, and natural bond orbital analysis were also performed. Prone reactive sites of the title compound have been identified by the molecular electrostatic surface potential and Fukui functions, which are mapped to the electron density surfaces. Hydrogen bond dissociation energies and bond dissociation energies for all other single bonds were further calculated for the EPYAPP molecule in order to examine the autoxidation mechanism and degradation properties. The title compound forms a stable complex with human alpha thrombin (PDB code: 1PPB) (binding energy -7.03 kcal/mol)) antagonist and could be a lead compound for developing new thrombin inhibitor or anti-thrombotic drugs.