Synthesis, Spectroscopic, Electronic and Molecular Docking Studies of Pyrazole Based Chalcones as Potential...

A series of pyrazole-based chalcone derivatives (DF1-DF6) were synthesized and characterized using spectroscopic (¹H/¹³C NMR, FT-IR) and computational methods. NMR analysis in acetone-d₆ revealed aromatic protons (7.0-8.1 ppm) and carbons (119-150 ppm), correlating well with DFT/B3LYP-D3/6-31G* calculations. FMO analysis showed energy gaps of 3.10-3.69 eV, with DF6 exhibiting the narrowest gap (3.11 eV) due to extended π-conjugation. TD-DFT predicted π→π* transitions (250-320 nm), where DF6 displayed the most red-shifted absorption (320.96 nm f_o = 1.40). Global reactivity descriptors (ω = 4.03-5.68; µ = 3.855-4.32 eV) underscored charge transfer potential. Molecular docking against the 1B38 protease identified DF1 as the top binder (- 10.6 kcal/mol), outperforming the standard inhibitor Saquinavir (- 7.6 kcal/mol), via π-anion/cation interactions with Lys A:33 and Asp A:145, supported by ESP maps. ADMET analysis revealed favorable drug-like properties: all compounds obeyed Lipinski's Rule, with moderate lipophilicity (logP = 3.586-4.34) with moderate absorption (Caco-2: -4.848 to - 5.163). DF1 showed balanced ADMET profiles, low CYP1A2 inhibition (0.24), moderate hERG risk (0.146), and high plasma protein binding (98.3%), while DF2 and DF5 exhibited higher toxicity (DILI probability > 0.83). Notably, binding affinity of DF1 surpassed Saquinavir by 3.0 kcal/mol, with stronger hydrogen bonding (3.02 Å vs. Saquinavir's 2.03-2.74 Å) and π-interactions. The experimental-theoretical consistency validates the models, positioning DF1 and DF6 as lead candidates. Future work should prioritize in vitro validation and structural optimization to enhance selectivity and ADMET properties. This integrated approach highlights pyrazole-chalcones as promising anticancer scaffolds, with DF1 having superior binding and moderate toxicity warranting further development.