Synthesis, crystal structure, in-silico ADMET, molecular docking and dynamics simulation studies of thiophene-chalcone analogues

Abstract

A novel thiophene-based chalcone derivatives, 3-(pyridin-4-yl)-1-(thiophen-2-yl)prop-2-en-1-one (Compound 1) and 3-mesityl-1-(thiophen-2-yl)prop-2-en-1-one (Compound 2) were synthesized and single crystals were grown using slow evaporation technique. The structure of the synthesized compound was confirmed using mass spectroscopy, 1H-NMR and FTIR spectroscopy. Single crystal X-ray structural analysis reveals that both crystals are crystallized under a monoclinic P21/n space group. C-H...O, C-H...Pi and Pi...Pi intra and intermolecular hydrogen bond interactions of compound 1 and C18-H18C...O7 (2.638 Å) and C3-H3...S1 (2.915 Å) intermolecular interactions in compound 2 contributed to molecular stability. The thiophene-chalcones analogues were screened for the in-sillico studies to understand the antibacterial activity. Molecular docking study was analyzed for the compound 1 and 2 with Penicillin binding proteins (PDB:1MWT) and Staphylocoagulase (PDB:1NU7) of MRSA. Compound 1 showed -6.0 kcal/mol for both Penicillin binding proteins and Staphylocoagulase while compound 2 showed the binding score -6.9 kcal/mol for 1MWT and -7.1 kcal/mol for 1NU7 protein, respectively. The crystallized compounds were also examined for their ADMET analysis and it was observed that there was no AMES toxicity in both compounds. Compound 1 and 2 were also showed 0.529 log mg/kg/day and 1.096 log mg/kg/day maximum tolerated dose (human), respectively. Ultimately, molecular dynamics simulation of compound 1 and 2 confirmed the best possible interaction and stability in the active site of INU7 and allosteric site of IMWT proteins for 20 ns.