New cyclopentaquinoline and 3,5-dichlorobenzoic acid hybrids with neuroprotection against oxidative stress for the treatment of Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative brain disease. Thus, drugs including donepezil, rivastigmine, and galantamine are not entirely effective in the treatment of this multifactorial disease. The present study evaluates eight derivatives (3a–3h) as candidates with stronger anti-AD potential but with less side effects. Reactive oxygen species (ROS) assays were used to assess oxidative stress which involve in the neurodegeneration. The neuroprotective properties of 3e against oxidative stress were done in three experiments using MTT test. The anti-AD potential was determined based on their anticholinesterase inhibition ability, determined using Ellman’s method, Aβ aggregation potential according to thioflavin (Th) fluorescence assay, and their antioxidative and anti-inflammatory activities. Compound 3e exhibited moderate cholinesterase inhibition activity (AChE, IC₅₀ = 0.131 µM; BuChE, IC₅₀ = 0.116 µM; SI = 1.13), significant inhibition of Aβ(1–42) aggregation (55.7%, at 5 µM) and acceptable neuroprotective activity. Extensive analysis of in vitro and in vivo assays indicates that new cyclopentaquinoline derivatives offer promise as candidates for new anti-AD drugs.

Keywords:

• acetylcholinesterase inhibitors
• Alzheimer’s disease
• molecular modelling
• Ellman’s method
• MTDL

Acknowledgements

The research was developed using the equipment purchased due to the Project "The equipment of innovative laboratories doing research on new medicines used in the therapy of civilization and neoplastic diseases" within the Operational Program Development of Eastern Poland 2007–2013, Priority Axis I Modern Economy, Operations I0.3 Innovation Promotion.

Institutional review board statement

The study was approved by the Local Ethics Committee of Medical University in Lodz for animal experiments permission no: 57/ŁB115/2018 Title: “Acute toxicity assessment of new tetrahydroacridine derivatives on a domestic mouse model in accordance with OECD 423” 13.11.2018.

Authors’ contributions

Conceptualisation, Methodology, Literature Review, Original Draft Preparation, Synthesis, Structure Analysis, Biological Tests (Ellman, Kinetics, beta-Amyloid, ABTS, DPPH), Analysis and Interpretation of all Results K.C. and P.Sz.; Hepatotoxicity, Neuroprotection and HYAL Analysis, M.G.; MS and IR analysis, R.S.; Molecular modelling, K.L., J.J. and M.B.; logP and pKa analysis, Editing, P.K.; In cellulo β-amyloid assay, A.E. and R.Sa.; Cell Analysis J.K. G.G. and I.M; Y3H system preparing, P.S.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

Financial support by grant [2015/19/B/NZ7/02847] from the National Science Centre, Poland is gratefully acknowledged. R. Sa. and A. E. thanks to the Spanish Ministerio de Economía y Competitividad by grant number [CTQ2017-88446-R].