Synthesis, X-ray crystal structures, spectroscopic characterization, DFT calculations, and molecular docking study of new N-(4-chlorobutanoyl)-N’-(2-, 3-, and 4-methoxyphenyl)thiourea derivatives

Herein, a series of new thiourea derivatives namely N-(4-chlorobutanoyl)-N’-(2-methoxy phenyl)thiourea (1a), N-(4-chlorobutanoyl)-N’-(3-methoxyphenyl)thiourea (1b) and N-(4-chloro butanoyl)-N’-(4-methoxyphenyl)thiourea(1c) have been synthesized and characterized by FT-IR,¹H and ¹³C NMR spectroscopic techniques. Single-crystal X-ray diffraction analysis revealed that 1a is monoclinic with P2₁/n space group, and 1b and 1c are triclinic with Pī space group. The isomerization effects of the methoxy groups in 1a-1c were significantly observed in crystal packing, the centrosymmetric dimer formed by a pair of N—H…S intermolecular hydrogen bonds in 1a and 1b isomers, while, in the 1c isomer, its crystal packing is linked by both N—H…O and N—H…S intermolecular hydrogen bonding interactions formed one-dimensional chains. DFT calculations have been implemented at the B3LYP/6-311++G(d,p) level of theory. The optimized geometrical parameters were compared with the experimental ones in the solid phase. NBO analysis reveals that the strongest donor-acceptor interactions correspond to electron donation between the lone pair (LP) on the thiourea nitrogen and the antibonding orbital π*_C=S in 1a-1c with energies in the range 56–90 kcal/mol. The molecular docking investigation is carried out to determine the inhibitory effect of the synthesized thiourea isomers against the COVID-19 coronavirus. The estimated binding energies between the 6LU7-main protease and 1a, 1b, and 1c isomers are −6.59, −6.87, and −6.74 kcal/mol, respectively.