Synthesis, spectra (FT-IR, NMR) investigations, DFT study, in silico ADMET and Molecular docking analysis of 2-amino-4-(4-aminophenyl)thiophene-3-carbonitrile as a potential anti-tubercular agent

Abstract

• Synthesis the studied compound. • Spectral (FT-IR and NMR) characterization. • Frontier Molecular Orbital. • NBO second perturbation energy investigations. • Population (ADCH and NBO) analysis. • Nonlinear optical (NLO) studies. • Pharmacological investigation. • Molecular docking studies against antitubacular agent. The title compound 2-amino-4-(4-aminophenyl)thiophene-3-carbonitrile ( AI3 ), was synthesized and characterized experimentally by FT-IR, NMR and theoretically by quantum chemical calculations. The results were compared and the analysis of the results showed mutual agreement between the experimental and theoretical data. The theoretical calculations were performed using Density Functional Theory (DFT) method, Becke-3-Parameter-Lee-Yang-Parr (B3LYP) in 6–311++ G (d,p) basis set. The Non Linear Optics (NLO), Natural Bond Orbital (NBO) including chemical reactivity parameters; Fukui function, Mulliken Population Analysis (MPA), Atomic Dipole Moment Corrected Hirshfeld (ADCH) population methods and the Natural Population Analysis were evaluated using the same level of theory. The results of the 3 population methods, MPA, NPA and ADCH were compared to examine charge distribution in the molecule. The Frontier Molecular Orbital indicated high bioactivity and NLO effects of the compound with a reduced value of the energy gap (-4.608103 eV) of the HOMO/LUMO which is also relatively comparable to its counterparts in the +1/-1 and +2/-2 states. The entire chemical reactivity analysis revealed C4 and N21 among the high donor atoms, then, S5 and C1 among the best acceptor atoms and this correlates with the location of the HOMO and LUMO in the studied compound. In addition, the antitubercular activities of the title compound against 3 (three) Mycobacterium tuberculosis proteins; 1P44, 1P45 and 4TZK were investigated using molecular docking simulations and the results were compared to those of Isoniazid (a standard anti-tubercular drug). AI3 showed greater binding affinities (-6.0, -3.9 and - 7.2 kcal/mol) in comparison to the Isoniazid drug (-5.5, -3.8 and -5.6 kcal/mol) for each target protein. Furthermore, an in silico study was performed to predict absorption, distribution, metabolism, excretion and toxicity profiles (ADMET) of the studied compound. The results reveal good to moderate anti-tubercular activity of the studied compound.