In this study, two diverse series of 2-aminothiazole-based multitarget compounds, one propenamide and the other propanamide derivatives, were designed and synthesized. Subsequently, their anticholinesterease and
antioxidant (ORAC) activities were tested. Among them, compound 3e was the most potent
acetylcholinesterase (AChE) inhibitor (AChE IC50 = 0.5 μM,
butyrylcholinesterase [BChE] IC50 = 14.7 μM) and compound 9e was the most potent BChE inhibitor (AChE IC50 = 3.13 μM, BChE IC50 = 0.9 μM). Kinetic experiments showed that both compounds were mixed-type inhibitors. According to the anticholinesterease activity results, five compounds (3e, 4e, 5e, 9d, and 9e) were selected for further activity studies, all of which are dual
cholinesterase inhibitors. Then, selected compounds were investigated in terms of their
metal chelation activity. Moreover, their
neuroprotective effects against H2 O2 -induced damage in the PC12 cell line were evaluated at 10 μM and the results showed that the
neuroprotective effect of 3e was 53% compared with the reference
ferulic acid (77%).
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) results of selected compounds revealed that the compounds were noncytotoxic. Additionally, 3e was more effective in reducing
lipopolysaccharides-induced interleukin-1β (IL-1β),
IL-6,
tumor necrosis factor-α (TNF-α), and
nitric oxide (NO) production in the human monocyte derived from patient with
acute monocytic leukemia cell line compared with other selected compounds. Finally, a molecular docking study was also performed.