Insight the confirmation of benzothiazolidinone-derived thiadiazole scaffolds as promising antiurease and anti-Alzheimer agents: synthesis, in vitro, and in silico investigations.

Abstract

Alzheimer's disease is a serious neurological disorder, and traditional therapies for Alzheimer's, like radiation and surgical procedures, as well as chemotherapeutics, are usually linked with multiple negative consequences. Finding a novel therapeutic anti-Alzheimer agent with high efficacy and minimal side effects, we have designed and synthesized benzothiazolidinone-derived thiadiazole-based Schiff base derivatives (1-15). Biological assessment of these compounds was carried out against acetylcholinesterase and butyrylcholinesterase, and all the derivatives showed varying degrees of inhibitory activity. Analog 8 (IC₅₀ = 3.60 ± 0.20 and 4.10 ± 0.20 μM for acetylcholinesterase and butyrylcholinesterase, respectively) demonstrated spellbinding efficacy in contrast to standard donepezil (IC₅₀ = 50 ± 0.10 and 8.10 ± 0.20 μM). The surpassing inhibition of analog 8 is due to highly reactive CF₃ moiety at the para-position, inhibiting the enzymes via strong hydrogen bond. Analog 7 with IC₅₀ value of 5.70 ± 0.10 and 6.20 ± 0.40 μM was also found with strong therapeutic potential than standard drug. The strong inhibition potential of lead compounds was also evaluated under enzyme kinetics and spellbinding potential was observed. Biological effectiveness of potent compounds was validated by visualizing the binding interactions via in silico molecular docking study and prediction of drug-likeness via ADME analysis. All the synthesized compounds were analyzed for their structural confirmation via ¹HNMR, ¹³CNMR, and HREI-MS.