Cinnamoyl-memantine hybrids: Synthesis, X-ray crystallography and biological activities

Herein, framework combinations of antioxidant substituted cinnamic acids and memantine (N-methyl-D-aspartate receptor antagonist) in a new multi-targeted chemical entity were described. The amide bond formation of the memantine hybrids 1-5 was performed by EDC/HOBt coupling reaction. The chemical structures of the synthesized compounds were confirmed by means of melting points, UV, IR, H-1 NMR, C-13 NMR, and HRMS. Additionally, the crystal structures of memantine hybrids (2 5) were also studied by single-crystal X-ray diffraction. The single-crystal X-ray analysis revealed that the compounds 2, 5 crystallize in a centrosymmetric manner both in monoclinic space group (SG) P2(1)/c, (No 14) and in a non-centrosymmetric manner for compounds 3 and 4, SG R3, (No 146) and SG P2(1)2(1)2(1), (No 19), respectively. Furthermore, preliminary in vitro screenings of their neuroprotective and radical scavenging activities were performed. The radical scavenging activity of synthesized memantine hybrids was measured against 1,1-diphenyl-2-picrylhydrazyl (DPPH center dot), hydroxyl (OH center dot) and superoxide (O2(center dot-)) radicals and compared with the standard antioxidants (ferulic and sinapic acids). Radical scavenging activity studies show that amongst the tested hybrids, N-sinapoyl amide of memantine (3) emerges as the most potent antioxidant in all tests. Moreover, in vitro evaluation of anti-Alzheimer effects showed that the obtained memantine hybrids displayed neuroprotection in the moderate levels. Generally, they possess a little weaker activity as compared to the positive control memantine. Taken together, our findings reveal that the N-sinapoylamide of memantine (3) can be considered as a promising neuroprotective agent for Alzheimer's disease, acting as well as a potent radical scavenger. (C) 2021 Elsevier B.V. All rights reserved.