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 (3a,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 ¹H-NMR, ¹³C-NMR, Fourier-transform infrared (FT-IR), and mass spectroscopic techniques. AChE and BChE enzyme inhibitions were obtained from the lowest Ki and IC₅₀ 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.