Badshah_2025_RSC.Adv_15_21700

This study is based on the synthesis and acetyl and butyryl cholinesterase inhibitory activities of some bis-Schiff base derivatives of 4-hydroxyacetophenone. All the synthesized products (2a-j) were structurally analysed by means of modern spectroscopic methods, including (1)H- and (13)C-NMR and EI-MS, and finally tested for their ability to inhibit cholinesterase enzymes. In the series, six compounds-2j (IC(50) = 15.86 +/- 0.38 and 29.23 +/- 0.04 microM), 2b (IC(50) = 18.58 +/- 0.21 and 35.31 +/- 0.01 microM), 2a (IC(50) = 44.36 +/- 0.33 and 77.93 +/- 1.46 microM), 2f (IC(50) = 48.37 +/- 0.06 and 76.35 +/- 1.17 microM), 2g (IC(50) = 62.28 +/- 0.42 and 98.71 +/- 1.18 microM), and 2e (IC(50) = 98.21 +/- 0.01 and 135.7 +/- 2.61 microM)-were found to be the most promising inhibitors of acetyl and butyryl cholinesterase enzymes compared with the standard drug galantamine (IC(50) = 104.8 +/- 1.83 and 156.8 +/- 1.83 microM), while the remaining compounds were found to be good-to-less active. Compound 2j displayed the most significant inhibition against AChE and BuChE among the tested bis-Schiff base derivatives, thus emerging as a superior compound to the standard galantamine. The highest activity of this compound is because of the favourable molecular interactions such as strong electrophilicity, high softness and a small energy gap. Molecular docking indicates that the compound 2j acts as a dual inhibitor owing to the formation of hydrophobic and polar interactions. The key structural features that include bromo benzyl and 2-methoxyphenol groups play a vital role in its efficacy, making it a more powerful inhibitor than the standard galantamine.