Design, synthesis and anti-acetylcholinesterase evaluation of new coumarin hybrids as potential agents for the treatment of alzheimer disease

Abstract

Acetylcholinesterase (AChE) is the primary enzyme responsible for the hydrolytic metabolism of the neurotransmitter acetylcholine (ACh). Acetylcholinesterase inhibitors (AChEIs) are found in the main class of drugs currently used for the treatment of Alzheimer‘s disease (AD). However, most of approved drugs have adversed side effects. Therefore, many compounds containing a coumarin scaffold have been assessed for their anti-AChE activity and becoming potential candidates for new anti-AD drugs. For this purpose, this research focused on the design of two different series of coumarin hybrids as potential agents for the treatment of AD by using molecular docking. Two series of novel coumarin-chalcone (201-214) and coumarin-imine (215-224) hybrids have been synthesized. The first step in this study is the synthesis of coumarin 155 and 160 via Pechmann condensation. Then, 4‘- hydroxychalcones (162-175) were synthesized by Claisen-Schmidt reaction of substituted benzaldehydes with 4-hydroxyacetophenone. Besides, imines (176-185) were synthesized from the reactions between substituted hydroxybenzaldehydes and substituted aniline. Chalcones (162-175) were converted to their o-alkylated derivatives (187-200). Finally, the reaction between coumarin 155 and o-alkylated derivatives (187-200) yielded 38.5-86.6%of hybrids (201-214), while hybrids (215- 224) were produced from the reaction of coumarin 160 and imines (176-185) in 29.8- 79.7% yields. The structures of the synthesized compounds were confirmed by spectroscopic techniques which include the IR and NMR (1H and 13C) analyses. The synthesized products were evaluated for their potential inhibitory effect on acetylcholinesterase (AChE) using Ellman‘s protocol. All of them exhibited excellent inhibitory activity against AChE. In coumarin-chalcone series, the IC50 values are in the range of 105.71-483.05 µg/mL. Hybrid 204 which carrying chloro group on ring-B of the chalcone scaffold was found as the most active compound having IC50 value of 105.71 ± 0.95 µg/mL. Nevertheless, in coumarin-imine series, the IC50 values were reported in 87.84-515.59 µg/mL, hybrid 218 having chloro on the ring-B and methoxy on the ring-A of the imine moiety with IC50 value of 87.84 ± 0.29 µg/mL showed the most potent as AChEIs. The reference drug, Galantamine yielded the IC50 of 496.18 ± 0.57 µg/mL. Furthermore, the molecular docking studies on both series were also performed to predict the binding modes of the compounds. Results exhibited that most of the designed compounds could bind to the peripheral anionic site (PAS) and catalytic active site (CAS) of the AChE.