Synthesis and Biological Activities of Novel Quinazoline–Sulfonamide Derivatives Promising for the Treatment of Alzheimer's Disease

Abstract Novel quinazoline–sulfonamide derivatives ( 4a ‐ n ) were synthesized and evaluated for their enzyme inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) which are associated with Alzheimer's diseases (AD). The target quinazoline–sulfonamides ( 4a ‐ n ) were obtained via one‐pot multicomponent reaction of 5‐amino‐1,3,4‐thiadiazole‐2‐sulfonamide ( 1 ) with substituted benzaldehydes ( 2a ‐ i ) and cyclohexane‐1,3‐diones ( 3 a , b ) under microwave irradiation. The reactions were performed using trifluoroacetic acid (TFA) as catalyst and methanol–water mixture as green solvent. All reactions were carried out in a short period of time and the products were obtained in moderate‐to‐high yields and their structures were confirmed using 1 H‐NMR, 13 C‐NMR, Fourier‐transform infrared (FT‐IR), and mass spectroscopic techniques. AChE and BChE enzyme inhibitions were obtained from the lowest Ki and IC 50 values. The lowest K i values of compounds 4j , 4d , 4e , and 4m were determined to be 4.84 ± 1.96 µM, 6.32 ± 1.75 µM, 7.21 ± 3.27 µM, and 7.48 ± 0.42 µM against AChE, while the lowest K i values of compounds 4d , 4f, and 4j were determined to be 4.74 ± 1.98 µM, 5.87 ± 2.11 µM, and 5.67 ± 1.96 µM against BChE, respectively. Finally, in silico molecular docking interactions were carried out by using AutoDock Vina software. The low binding energy values of the compounds ( 4a ‐ 4n ) against AChE and BChE enzymes indicated their high inhibitory effectiveness.