Click Chemistry Synthesis of Tetrazole linked Organosilanes and Organosilatranes: A computational Evaluation of Pharmacokinetics, Bioactivity, and Acetylcholinesterase (AChE) Inhibition for Alzheimer’s Treatment

Abstract

Tetrazole compounds are versatile scaffolds with significant biological properties, often serving as bioisosteres for cis-amide linkages in peptidomimetics and as substitutes for carboxylic acids. However, despite their extensive applications in medicinal chemistry, the potential of integrating tetrazole units with organosilicon frameworks remains largely unexplored, particularly for addressing neurodegenerative disorders like Alzheimer’s disease (AD).

This research aimed to synthesize tetrazole-allied organosilanes and organosilatranes, investigate their structural transformations, and assess their potential biological applications, particularly in the treatment of AD.

The synthesis of tetrazole-allied organosilanes and organosilatranes was achieved using a ZnBr₂-catalyzed click chemistry approach and transesterification reactions. The compounds were characterized by infrared (IR) spectroscopy, proton (¹H) and carbon (¹³C) nuclear magnetic resonance (NMR) spectroscopy, and mass spectrometry. Pharmacokinetic profiles, bioactivity scores, and toxicity assessments were conducted using MOLINSPIRATION, PreADMET, and GUSAR ONLINE tools. Molecular docking studies were performed to evaluate the inhibitory activity of the synthesized compounds against human acetylcholinesterase (AChE).

The synthesized tetrazole-allied compounds exhibited promising pharmacokinetic properties, bioactivity scores, and low toxicity profiles. Molecular docking studies indicated that all synthesized compounds showed strong inhibitory activity against human AChE with a binding energy of -9.50 kcal/mol, -10.06 kcal/mol, -9.76 kcal/mol and -8.32 kcal/mol, suggesting potential efficacy of compounds in AD treatment.

By addressing the research gap in the synthesis and application of tetrazole-based organosilicon compounds, the study highlights their potential in biological applications, particularly as candidates for AD treatment.