Organohalogen chalcones: design, synthesis, ADMET prediction, molecular dynamics study and inhibition effect on acetylcholinesterase and carbonic anhydrase

In an effort to discover potential acetylcholinesterase (AChE) and carbonic anhydrase (CA) inhibitors, a novel series of organohalogen chalcone derivatives (12–20, 23–30) was synthesized, and their chemical structures were characterized by spectral analysis. They showed a highly potent inhibition effect on AChE and hCAs (K_i values range from 5.07 ± 0.062 to 65.53 ± 4.36 nM for AChE, 13.54 ± 2.55 to 94.11 ± 10.39 nM for hCA I, and 5.21 ± 0.54 to 57.44 ± 3.12 nM for hCA II). In addition, the chalcone derivatives with the highest inhibitor score docked into the active site of the indicated metabolic enzyme receptors, and their absorption, metabolism, and toxic properties were evaluated according to ADMET's estimation.Compounds 16 and 19 exhibited the highest inhibition score, emerged as lead compounds, and inspired the development of more potent compounds.