Synthesis, characterization, crystal and molecular structure and theoretical study of N-(naphthalen-1-yl)-2-(piperidin-1-yl) acetamide, a selective butyrylcholinesterase inhibitor

Abstract

In this study, we reported for the first time the crystalline and molecular structure of the compound N-(naphthalen-1-yl) -2- (piperidin-1-yl) acetamide. The synthesis of the compound was carried out by amidation using a coupling reagent (N, N'-diisopropylcarbodiimide) and subsequently amination. The compound was experimentally characterized by UV-visible spectroscopy, 13C-NMR, 1H-NMR, melting point, and X-ray diffraction technique. In addition, we include here, theoretical studies on boundary molecular orbitals, descriptors global reactivity, natural bond orbital analysis, Hirshfeld surface analysis, energy framework and molecular docking. Interestingly, acetamide shows a keto form in the solid state, as reported in similar monosubstituted acetamide compounds. The dihedral angles are negligible, being essentially coplanar between the fragment. Additionally, inhibitory activity studies were carried out for the enzymes acetylcholinesterase and butyrylcholinesterase, obtaining an IC50 of 426.14 ± 18.54 µM and 5.12 ± 0.02 µM, respectively, thus having significant selectivity for butyrylcholinesterase with an IC50 lower than that reported for the reference compound galantamine (7.96 ± 0.8 µM). Our consistent molecular coupling analyzes show the formation of a more stable complex between compound 5 and butyricholinesterase due to the complementary interactions of compound 5′s naphthyl ring with residues Trp 231 and Phe 329 compared to the complex formed with acetylcholinesterase.