Synthesis, structure elucidation, SC-XRD/DFT, molecular modelling simulations and DNA binding studies of 3,5-diphenyl-4,5-dihydro-1 <i>H</i> -pyrazole chalcones

Deoxyribonucleic acid (DNA) acts as the most important intracellular target for various drugs. Exploring the DNA binding interactions of small bioactive molecules offers a structural guideline for designing new drugs with higher clinical efficacy and enhanced selectivity. This study presents the facile synthesis of pyrazoline-derived compounds <b>(4a)-(4f)</b> by reacting substituted chalcones with hydrazine hydrate using formic acid. The structure elucidation of substituted pyrazoline compounds was carried out using ¹H-NMR, FT-IR and elemental analyses. While the crystal structures of two compounds <b>(4a)</b> and <b>(4b)</b> have been resolved by single-crystal X-ray diffraction (SC-XRD) analysis. Hirshfeld surface analysis also endorsed their greater molecular stability. Computational calculations at DFT/B3LYP/6-311++G(d,p) were executed to compare the structural properties (bond angle and bond length) and explore reactivity descriptors, frontier molecular orbitals (FMO), Mulliken atomic charges (MAC), molecular electrostatic potential (MEP) and electronic properties. All the compounds were evaluated for DNA binding interactions by UV-Vis spectrophotometric analysis. The results revealed that compounds <b>(4a)-(4f)</b> bind to DNA <i>via</i> non-covalent binding mode having binding constant values ranging from 1.22 × 10³ to 6.81 × 10⁴ M^-1. The negative values of Gibbs free energy also proved the interaction of studied compounds with DNA as a spontaneous process. The findings of molecular docking simulations depicted that these studied compounds showed significant binding interactions with DNA and these results were consistent with experimental findings. Compound <b>(4b)</b> was concluded as the most potent compound of the series with the highest binding constant (4.95 × 10⁴) and strongest binding affinity (-8.48 kcal/mol).Communicated by Ramaswamy H. Sarma.