New thiophene pyrazole hybrid: An efficient synthesis, X-ray analysis, computational and in silico studies

Abstract

A one-pot, three-component synthesis of ethyl 5-(3-ethoxy-3-oxopropanoyl)-4-phenyl-2-(phenylamino)thiophene-3-carboxylate (7) was reported. Its reaction with DMF-DMA and phenylhydrazine produced a thiophene pyrazole hybrid 8. The chemical structures of the synthesized compounds were confirmed using spectral (IR, NMR, MS) and elemental analysis. Additionally, the 3D structure of compound 8 was confirmed by single-crystal X-ray diffraction. The crystallographic study revealed that compound 8 is mainly stabilized by weak C–H•••O and C–H•••N contacts together with dispersive interactions. Hirshfeld surface analysis revealed that crystal packing is dominated by H•••H (57.9%), C•••H (18.6%), and O•••H (10.6%) interactions. DFT calculations for compounds 7 and 8 support experimental interpretation. MEP surface showed that carbonyl oxygen atoms are the richest regions, while FMO analysis indicated moderate HOMO/LUMO gaps (4.032 for 7 and 4.125 eV for 8), consistent with a stable and polarizable conjugated system. NBO and Mulliken charge analyses are consistent with MEP results. In silico ADME prediction was performed to evaluate the physicochemical and pharmacokinetic properties of the synthesized compounds. Molecular docking studies were conducted against the EGFR protein (PDB ID: 5UGB) to investigate their potential as anticancer leads. The results revealed that compound 7 exhibited the most favorable predicted binding activity, while both compounds demonstrated binding patterns and affinities comparable to the reference drug.