Tamaddon-Abibigloo_2024_Bioorg.Chem_147_107355

Multi target directed ligands (MTDLs) are one of the promising tools for treatment of complex disease like Alzheimer's disease (AD). In this study, using rational design, we synthesized new 15 hybrids of the s-triazine, isatin and aniline derivatives as anti- AD compounds. The design was as way as that new compounds could had anti cholinesterase (ChE), antioxidant and biometal chelation ability. In vitro biological evaluation against ChE enzymes showed that these molecules were excellent inhibitors with IC(50) values ranging from 0.2 nM to 734.5 nM for acetylcholinesterase (AChE), and 0.02 microM to 1.92 microM for butyrylcholinesterase (BChE). Among these compounds, 8 l with IC(50 AChE) = 0.7 nM, IC(50 BChE) = 0.09 microM and 8n with IC(50 AChE) = 0.2 nM, IC(50 BChE) = 0.03 microM were the most potent compounds. In silico studies showed that these molecules had key and effective interactions with the corresponding enzymes residues. The molecules with hydroxyl group on aniline moiety had also good antioxidant activity with EC(50) values ranging from 64.2 microM to 103.6 microM. The UV-Vis spectroscopy study revealed that molecule 8n was also able to chelate biometals such as Zn(2+), Cu(2+)and Fe(2+) properly. It was concluded that these molecules could be excellent lead compounds for future studies.