Synthesis, Spectral Analysis and Molecular Docking Investigation of Thiadiazole Based Sulfonamide Derivatives: An Effective Approach Toward Alzheimer's Disease

Alzheimer's disease (AD), a neurodegenerative condition is expected to affect 152 million in 2050. The current study comprises the evaluation of thiazole based thiadiazole bearing sulfonamide derivatives to treat Alzheimer's disease. A series of compounds (1-15) were synthesized and were studied for their anti-Alzheimer's potential. Their IC50 values lie in the range between (19.20 +/- 0.20 nM-2.50 +/- 0.20 nM) for AChE and (19.80 +/- 0.20 nM-3.30 +/- 0.50 nM) for AChE. Among all of them, analog 2, 7, 9, and 15 were reported to possess significant activity. Among all the members of series, compound 15 having IC50=2.50 +/- 0.20 nM and 3.30 +/- 0.50 nM for AChE and BuChE, respectively, emerged as the most promising candidate due to the presence of two electronegative fluorine (F) atoms. The small and highly electronegative fluorine atoms have the ability to block the enzyme's activity by forming strong hydrogen bonds with the amino acids of the target enzymes, thereby inhibiting their function. The efficacy of these novel compounds was studied in comparison to the standard drug donepezil having IC50=5.80 +/- 0.30 nM for AChE and IC50=6.30 +/- 0.81 nM BuChE. For further assessment of inhibition potential and mode of inhibition, molecular docking study of all the potent compounds was carried out. Further, the structural identity of the synthesized compounds was confirmed using various spectroscopic techniques, including H-1-NMR, C-13-NMR, and High-Resolution Electron Impact (HREI) Mass spectrometry, which provided detailed information about their molecular structure. ADME analysis of all the synthesized compounds confirmed their potential as drugs, indicating favorable pharmacokinetic properties and a promising drug profile.