Synthesis, characterization, molecular docking and molecular dynamics simulations of novel 2,5-disubstituted-1,3,4-thiadiazole derivatives as potential cholinesterase/monoamine oxidase dual inhibitors for Alzheimer’s disease

Designing multi-targeted drugs (MTD) for Alzheimer’s disease (AD) is now one of the priorities for medicinal chemists, as the disease has a complicated not fully understood pathological nature and the approved mono-targeted drugs only alleviate the symptoms. In this study, the synthesis, spectral analyses and <i>in vitro</i> inhibition activity against cholinesterase (ChE) and monoamine oxidase (MAO) enzymes of a novel series of <i>N</i>-[5-(adamantan-1-yl)-1,3,4-thiadiazol-2-yl]-2-(4-un/substituted) cyclic secondary amino-acetamide/propanamide derivatives were done. Generally, derivatives were more selective against acetylcholinesterase (AChE) and <i>h</i>-MAO-B than butyrylcholinesterase (BChE) and <i>h</i>-MAO-A, respectively. Derivatives <b>4a</b>, <b>4b</b>, <b>3a</b>, <b>3d</b> and <b>3b</b> ordered from the most potent to the least displayed significant inhibition against AChE. Also, derivatives <b>4a</b>, <b>4b</b> and <b>3a</b> still maintained their significant inhibition against <i>h</i>-MAO-B in the same potency order, making them dual inhibitors and MTD candidates for AD. Binding interactions with several crucial amino acid residues for activity and selectivity as well as the stability of the most active derivatives-enzyme complex were confirmed utilizing molecular docking and molecular dynamic simulation studies. Communicated by Ramaswamy H. Sarma Novel 2,5-disubstituted-1,3,4-thiadiazole derivatives were synthesized. The ChEs/MAOs dual inhibition activity against Alzheimer’s disease was tested. Compounds <b>4a</b>, <b>4b</b> and <b>3a</b> were active dual inhibitor against both AChE and <i>h</i>-MAO-B. Compounds <b>3d</b> and <b>3b</b> were also active against AChE. No significant inhibition activity against BChE and <i>h</i>-MAO-A.