Novel tetrahydroacridine derivatives with iodobenzoic acid moiety as multifunctional acetylcholinesterase inhibitors

Abstract

New synthesized series of 9-amino-1,2,3,4-tetrahydroacridine derivatives with iodobenzoic acid moiety were studied for their inhibitory activity toward cholinesterase and against β-amyloid aggregation. All novel molecules 3a-3i interacted with both cholinesterases-acetylcholinesterase and butyrylcholinesterase-delivered nanomolar IC values. The structure-activity relationship showed that N-butyl moiety derivatives are stronger inhibitors toward AChE and BuChE than N-ethyl and N-propyl moieties compounds. The most potent compound toward acetylcholinesterase was inhibitor 3f (IC = 31.2 nm), and it was more active than reference drug, tacrine (IC = 100.2 nm). Compound 3f showed strong inhibition of butyrylcholinesterase (IC = 8.0 nm), also higher than tacrine (IC = 16.3 nm). In the kinetic studies, compound 3f revealed mixed type of acetylcholinesterase inhibition. The computer modeling was carried out. The most active compound 3f was confirmed as peripheral anionic site inhibitor of acetylcholinesterase. Moreover, molecule 3f inhibited β-amyloid aggregation (at the concentration 10 μm-24.96% of inhibition, 25 μm-72%, 50 μm-78.44%, and 100 μm-84.92%). Therefore, among all examined, compound 3f is the most promising molecule for further, more detailed research of novel multifunctional agents in the therapy of Alzheimer's disease.

Novel tetrahydroacridine derivatives with iodobenzoic moieties induce G0/G1 cell cycle arrest and apoptosis in A549 non-small lung cancer and HT-29 colorectal cancer cells

“…The synthesis of novel tetrahydroacridine derivatives with iodobenzoic moieties (Scheme 1) was described previously in publication by Skibiński et al [33]. At the beginning, the 2-chloro-4,6-dimethyl-1,3,5-triazine (CDMT) in THF (10 mL), 2-iodobenzoic acid, 3-iodobenzoic acid or 4-iodobenzoic acid and dropwise N-methylmorpholine were mixed together at temperature − 10 °C.…”

“…The influence of novel kind of moieties on anticancer activities of tetrahydroacridine derivatives was investigated. The synthesis of novel tetrahydroacridine compounds with iodobenzoic acid moiety was described previously [33]. The aim of this study was to determine the cytotoxic activity of 9 novel tetrahydroacridine derivatives on A549, HT-29 cell lines, to investigate their biological properties and molecular mechanism of action.…”

Physicochemical evaluation of new tetrahydroacridine and iodobenzoic acid hybrids as the next step in the design of potential drugs for treating Alzheimer's disease

“…Now, pharmacotherapy, which slows down the progress of AD, is being used. In an earlier study, Skibiński et al (Skibiński et al, 2018) developed a new tetrahydroacridine derivative that exhibited an inhibitory activity against acetylcholinesterase and beta‐amyloid aggregation. Such multitarget‐directed ligands offer hope for AD therapy by decreasing the symptoms of the disease and making the therapy simpler.…”

“…In this study, we developed assays that evaluate basic physicochemical properties of a series of compounds developed by (Skibiński et al, 2018) (Figure 1). Moreover, we developed quantitative methods with validation and stability tests for determining the most biologically active compound in this series.…”

“…More advanced pharmacokinetic studies require advanced quantitative methods; therefore, we developed a simple isocratic HPLC method for the spectrophotometric quantification of the most biologically active compound in the series developed by Skibiński et al (Skibiński et al, 2018). Full validation was performed according to the ICH guidelines Q2(R1) (ICH, 2005).…”