Synthesis and biological studies of acetophenone-based novel chalcone, semicarbazone, thiosemicarbazone and indolone derivatives: Structure-Activity relationship, molecular docking, molecular dynamics, and kinetic studies

This study presents the synthesis and evaluation of nine acetophenone derivatives (1–9), with compounds 2, 4, 5, 6, 7, and 9 being novel and synthesized for the first time. These derivatives encompass diverse structural motifs including chalcone, thiosemicarbazone, semicarbazone, and indolone derivatives. The structures of synthesized compound were confirmed by NMR analysis. The synthesized compounds were assessed for their in vitro enzyme inhibition against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α-Glycosidase enzymes, as well as their antioxidant capacities using the DPPH radical scavenging assay. With Ki values ranging from 8.96±0.40 to 44.16±4.25 nM, these showed effective inhibition of AChE. However, the inhibitory characteristics of all drugs were almost the same. The Ki values of the two most active compounds, (3) and (4), were 8.96±0.40 and 11.33±0.58 nM, respectively. Regarding α-Glycosidase, they demonstrate that all novel compounds (1–9) have IC50 values between 30.16 and 133.98 µM, whereas the Ki values vary from 42.71±5.90 to 128.78±8.03 µM. Compound 4 emerged as a notable inhibitor, displaying significant inhibition against all used enzymes. Molecular docking studies revealed its exceptional binding affinities, corroborated by MM-GBSA ΔG binding free energies, and Glide Emodel scores. Compound 7 also exhibited promising inhibitory potential against α-Glycosidase. Docking scores for hAChE -12.207, for hBChE -10.140 and for α-Glycosidase -10.590 kcal/mol. The 250 ns molecular dynamics simulations confirmed the stability of the ligand-protein complexes, particularly with compound 4. The ligand-protein complexes were found extremely stable according to the MD simulations. Additionally, ADME predictions indicated favorable pharmacokinetic properties and drug-likeness for all compounds, further supporting their potential as orally active agents. Compound 4, in particular, stands out as a multitarget drug candidate, with strong inhibition against key enzymes implicated in neurodegenerative diseases and diabetes, suggesting its therapeutic potential in these conditions.