Dual inhibition of S. aureus TyrRS and S. aureus gyrase by two 4-amino-4′-acetyldiphenyl sulfide-based Schiff bases: Structural features, DFT study, Hirshfeld surface analysis and molecular docking

Abstract

• Structural description of two 4-amino-4′-acetyldiphenyl sulfide-based Schiff bases and optimization of their molecular structures by the B3LYP / 6-31G(d) and B3LYP / cc-pvdz methods. • Calculation of their IR frequencies and assignment of the vibration modes, estimation of their Mulliken charges and evaluation of their frontier molecular orbitals. • Hirshfeld surface analysis of the leading non-covalent interactions and non-classical contacts. • Molecular docking studies on S. aureus tyrosyl-tRNA synthetase, S. aureus topoisomerase II DNA gyrase as targets, and In silico investigation of the binding interactions in the proteins’ binding pockets. • Dual promising inhibition of both receptors by both studied ligands. Two 4-amino-4′-acetyldiphenyl sulfide-based Schiff bases, namely 1-[4-({4-[(E)-(2-hydroxynaphthalen-1-yl)methylideneamino]phenyl}sulfanyl)-phenyl]ethanone ( I ) and (E)-1-[4-({4-[(4-methoxybenzylidene)amino]phenyl}-sulfanyl)phenyl]ethan-1-one ( II ) were structurally studied. They crystallize respectively in the monoclinic Cc and the triclinic P 1 space groups, with the respective cell parameters: [10.695(3) Å, 44.458(14) Å, 4.4437(11) Å, 99.004(9)°] and [5.7708(2) Å, 8.0867(3) Å, 19.6929(8) Å, 81.844(2)°, 86.664(3)°, 85.662(3)°]. The asymmetric units of ( I ) and ( II ) are composed of one molecule and two crystallographically independent molecules, respectively. Their molecular structures were optimized by the density functional theory and correlated correspondingly to the crystal structures. Moreover, the IR vibration modes were assigned to the calculated wavenumbers, the Mulliken atomic charges obtained and the frontier molecular orbitals evaluated. The hydrogen bonding and the non-classical intermolecular interactions within the two frameworks were investigated using Hirshfeld surface analysis which indicated the presence of C H…H C, C H···π, C H···O, C H···N, C H···S and π··· lp interactions as well as π···π stacking. Additionally, in order to understand the interacting binding sites of the two molecules with the bacterial S. aureus protein receptors, the studied compounds were in silico evaluated by molecular docking against tyrosyl-tRNA synthetase 1JIJ and topoisomerase II DNA gyrase 2XCT enzymes. The results revealed consequently potent antimicrobial efficacy through the formed hydrogen bonds, hydrophobic contacts, π-cation interactions and π…π stacking.