Multifunctional iminochromene-2H-carboxamide derivatives containing different aminomethylene triazole with BACE1 inhibitory, neuroprotective and metal chelating properties targeting Alzheimer's disease

Eur J Med Chem. 2017 Dec 1:141:690-702. doi: 10.1016/j.ejmech.2017.09.057.

Aida Iraji ¹, Omidreza Firuzi ¹, Mehdi Khoshneviszadeh ², Marjan Tavakkoli ¹, Mohammad Mahdavi ³, Hamid Nadri ⁴, Najmeh Edraki ⁵, Ramin Miri ⁶

Affiliations

1 Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
2 Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Medicinal Chemistry, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
3 Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
4 Department of Medicinal Chemistry, Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
5 Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address: edrakin@sums.ac.ir.
6 Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address: ramin.miri.15@gmail.com.

PMID: 29107423 DOI: 10.1016/j.ejmech.2017.09.057

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder known for the presence of amyloid beta plaques resulting from the sequential action of β-secretase and γ-secretase on amyloid precursor protein. We developed and synthesized, through click reactions, a new family of iminochromene carboxamides containing different aminomethylene triazole. The BACE1 inhibition, neuroprotective capacity and metal chelation of these derivatives make them ideal candidates against AD. Most of the synthesized compounds were shown to have potent BACE1 inhibitory activity in a FRET assay, with an IC₅₀ value of 2.2 μM for the most potent compound. Moreover, molecular modeling evaluation of these BACE1 inhibitors demonstrates the vital role of the amine and amide linkers through hydrogen bond interactions with key Amino acids in the BACE1 active site. Our in vitro neuroprotective evaluations in PC12 neuronal cells of Aβ-induced neuroprotection demonstrated promising activity for most of the compounds as neuroprotective agents. Based on our findings, we propose that introduction of a phthalimide substitute on the triazole ring shown to be interesting multifunctional lead compound worthy of further study.

Keywords

BACE1 inhibitor; Click reaction; Metal chelator; Molecular modeling; Neuroprotective assay; Synthesis.

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