Acetylcholinesterase (AChE) is a critical enzyme, in Alzheimer's disease (AD) progression and hence has been subjected to intense drug discovery programme. Here, we report synthesis and testing of pyrimidine derivatives in conjugation with triazolopyrimidine based hybrid scaffold of AChE inhibitors for development of new molecules towards the treatment of AD. We used a multipronged approach employing computational, chemical and biological approaches to find the best inhibitor of AChE. Three molecules (10 e, 11 c and 12 b) derived from this scaffold inhibited AChE in nanomolar to micromolar range. Highest activity was shown by 2‐(4‐(6‐(quinolin‐8‐yloxy)pyrimidin‐4‐yl) piperazin‐1‐yl)nicotinonitrile (12 b) which has IC50 value of 36 nM. Inhibitory effect of 12 b was stronger for human AChE in neuronal cell extract compared to eelAChE. This activity is comparable to donepezil (IC50=38nM) which is considered as good standard among AChE inhibitors. The inhibitory activity of 12 b was also in agreement with molecular simulation studies which showed stable interaction of the 12 b with the catalytic active site as well as peripheral anionic site. Molecular simulation studies also indicated stronger interaction of 12 b with rhAChE than TcAChE. This was later confirmed in studies with neuronal cell extract where compound 12 b showed enzyme inhibition at 25 nM. Further this molecule was not found to be toxic or carcinogenic.

The copper(II) saccharinate complex containing pyridine and dmf have been prepared and characterized by elemental analyses, IR, UV-Visible, magnetic measurements, thermal analysis and single crystal X-ray diffraction methods. The crystal structure of aqua-bis(pyridine)di(saccharinato)copper(II) [Cu(sac)2(py)2(H2O)] and diaqua-(dimethylformamide)-di(saccharinato)copper(II) [Cu(sac)2(H2O)2(dmf)] (sac = saccharinate anion; py = pyridine and dmf = dimethylformamide) have been determined. The compounds crystallize in the orthorhombic space group Iba2 with Z = 4 and the Cu(II) ion presents a CuN4O square pyramidal coordination sphere. Two one-electron electrochemical redox processes have been followed by both of the complexes.