Design and synthesis of 1,2,3-triazole thiadiazole hybrids with in vitro and in silico evaluation of their anti-inflammatory and anti-alzheimer activities.

Nano technology possesses a role in the enhancement of anti-inflammatory and anti-Alzheimer activities of the synthesized triazole/thiadiazole hybrids 3a-c. Selective propargylation of 5-amino-1,3,4-thiadiazole-2-thiol with propargyl bromide and triethyl amine followed by Click reaction with different azides to afford 1,2,3-triazole/thiadiazole hybrids 3a-c. The structure of the synthesized compounds was confirmed using different spectroscopic analysis such as FT-IR, 1H NMR,13C NMR and elemental analysis. Moreover, the synthesized compounds were prepared in nano scale via chitosan to enhance their solubility and compatibility, and their size was evaluated via transmission electron microscope (TEM). The formulated nanoparticles are found to be relatively stable with higher positive zeta potential 22.5-29.5 mV and particle size 29-80 nm. The studied compounds were further subjected to molecular docking in the active site of four particular proteins AChE, BuChE, LOX-5 and COX-2.The synthesized compounds and their nanoformulations were tested as anti-inflammatory and anti-Alzheimer as acetylcholinesterase inhibitors. The result revealed that nanoformulations N-(3a-c) exhibited superior inhibitory activity compared to their synthesized counterparts 3a-c, demonstrating enhanced potency against AChE, BuChE, NO formation, iNOS, LOX-5, and RBC lysis. N-3a showed the strongest iNOS inhibition, while N-3b was the most effective BuChE inhibitor. Notably, all nanoformulations matched the reference drug in LOX-5 inhibition and outperformed diclofenac K in protecting against RBC lysis. These results highlight the potential of these hybrids as anti-inflammatory and anti-Alzheimer agents.