Design, synthesis, in vitro and in silico evaluations of new isatin-triazine- aniline hybrids as potent anti- Alzheimer multi-target directed lead compounds

[Display omitted] •Novel isatin-1,3,5-triazine-aniline derivatives hybrids were designed and synthesized as anti-Alzheimer agents.•These compounds were evaluated as multi-target directed ligands (MTDLs) for in vitro anti-cholinesterase (ChEs) potency, antioxidant activity and biometal chelation ability.•Compound 8l and 8n showed the acceptable activity against mentioned targets and had potency to be considered as lead compounds. 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 IC50 values ranging from 0.2 nM to 734.5 nM for acetylcholinesterase (AChE), and 0.02 μM to 1.92 μM for butyrylcholinesterase (BChE). Among these compounds, 8 l with IC50 AChE = 0.7 nM, IC50 BChE = 0.09 μM and 8n with IC50 AChE = 0.2 nM, IC50 BChE = 0.03 μM 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 EC50 values ranging from 64.2 μM to 103.6 μM. The UV–Vis spectroscopy study revealed that molecule 8n was also able to chelate biometals such as Zn2+, Cu2+and Fe2+ properly. It was concluded that these molecules could be excellent lead compounds for future studies.