Novel asymmetric biscarbothioamides as Alzheimer's disease associated cholinesterase inhibitors: synthesis, biological activity, and molecular docking studies

Abstract

Exploring novel frameworks for treating Alzheimer's disease is an ambitious objective. In this particular context, a range of asymmetric biscarbothioamide derivatives (3a–l) with varying substitutions have been meticulously designed and effectively synthesized. The newly synthesized compounds have all been definitively characterized using established spectroscopic techniques such as ¹H-NMR, ¹³C-NMR, FT-IR, and elemental analysis. In vitro, all the derivatives (3a–l) were evaluated to assess their inhibitory potential against cholinesterase enzymes (acetylcholinesterase, AChE, and butyrylcholinesterase, BChE). The outcomes demonstrated that these derivatives were potent and exhibited selectivity in inhibiting AChE, except for compounds 3b and 3e, which specifically inhibited BChE, showcasing varying degrees of K_I values. Significantly, compounds 3j (K_Is of 11.91 ± 2.25 nM for AChE and 77.76 ± 8.02 nM for BChE) and 3h (K_Is of 14.73 ± 2.30 nM for AChE and 59.54 ± 6.20 nM for BChE) emerged as the most potent dual inhibitors of AChE and BChE within the series, respectively, with K_I constants even lower than those of the standard drug tacrine (K_Is of 68.70 ± 5.39 nM for AChE and 111.60 ± 10.52 nM for BChE). Furthermore, their potential scavenging activity against DPPH and ABTS radicals was evaluated. To further validate the experimental findings, molecular docking studies were performed in silico to ascertain the binding modes of these compounds with the active pockets of AChE and BChE enzymes.