Newly synthesized Bis-Hydrazono[1,3,4] thiadiazoles as Anti-Alzheimer’s Agents: Greener past and In-Vitro acetylcholinesterase inhibition assay investigations

[Display omitted] The designed and synthesized multifunctional properties of bis-hydrazono[1,3,4]thiadiazoles became important for developing an efficient medication for Alzheimer’s disease. Thiadiazoles were characterized and studied towards this target as an acetylcholinesterase inhibitor (ChEIs). In this study, one-pot synthetic strategy was applied for the synthesis of bis-hydrazono[1,3,4]thiadiazole series from 2,2′-(1,2-diphenylethane-1,2-diylidene)bis(hydrazine-1-carbodithioic acid) and hydrazonoyl chlorides. The greener pastures, in silico, an environmentally-friendly and free computer-aided method, bioactivity studies of the bis-hydrazono[1,3,4]thiadiazoles 4a-h exhibited various possible interesting inhibitory activities against AChE showing similar behaviour to the approved drugs, Donepezil, Galantamine and Rivastigmine. For a fair comparison, the superpositions of 4a-h, and Donepezil, Galantamine and Rivastigmine docked together into the functional domain (binding pocket) of 1EVE to reveal interesting different molecular laydowns of the compounds. On the other side, the display of the molecules before and after docking was discussed. The binding affinity slightly differs between Donepezil, Galantamine, Rivastigmine, and the ligands 4a-h. The range of the recorded binding affinity for 4a-h is from (−9.4 to −8.4 kcal/mol−1), whereas the binding affinity for Donepezil, Galantamine and Rivastigmine is (−11.1, −9.8 and −8.0 kcal/mol−1 respectively), which is higher than all the prepared ligands. Furthermore, the binding amino acids also varied among the studied compounds in this study. Phe290, Phe330, Phe331, Trp279, Tyr70, Tyr121 and Tyr334 are the common amino acids binding with the FDA-approved AChE inhibitors for treating AD, Donepezil, Galantamine and Rivastigmine and ligands. Notably, the number of hydrophobic and hydrogen interactions studied between the ligands 4a-h and the Donepezil, Galantamine and Rivastigmine drugs were compared as a preliminary indicator towards a successful inhibitor. The comparative study in this research work aims to rank our compounds with respect to the approved medications. This is a friendly environmental preliminary helpful indication before leaping into time and energy-consuming experimental work. Organ toxicological endpoints and toxicity-predicted activity were obtained using the ProTox-II web server for both the approved medication and ligands. Later, in-vitro acetylcholinesterase inhibition assays were cond