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. 2019 Jan 24;20(3):498.
doi: 10.3390/ijms20030498.

Discovery of New Cyclopentaquinoline Analogues as Multifunctional Agents for the Treatment of Alzheimer's Disease

Kamila Czarnecka  1 , Małgorzata Girek  2 , Paweł Kręcisz  3 , Robert Skibiński  4 , Kamil Łątka  5 , Jakub Jończyk  6 , Marek Bajda  7 , Jacek Kabziński  8 , Ireneusz Majsterek  9 , Piotr Szymczyk  10 , Paweł Szymański  11
Affiliations

Discovery of New Cyclopentaquinoline Analogues as Multifunctional Agents for the Treatment of Alzheimer's Disease

Kamila Czarnecka et al. Int J Mol Sci. .

Abstract

Here we report the two-step synthesis of 8 new cyclopentaquinoline derivatives as modifications of the tetrahydroacridine structure. Next, the biological assessment of each of them was performed. Based on the obtained results we identified 6-chloro-N-[2-(2,3-dihydro-1H-cyclopenta[b]quinolin-9-ylamino)-hexyl]]-nicotinamide hydrochloride (3e) as the most promising compound with inhibitory potencies against EeAChE and EqBuChE in the low nanomolar level 67 and 153 nM, respectively. Moreover, 3e compound is non-hepatotoxic, able to inhibit amyloid beta aggregation, and shows a mix-type of cholinesterase's inhibition. The mixed type of inhibition of the compound was confirmed by molecular modeling. Then, yeast three-hybrid (Y3H) technology was used to confirm the known ligand-receptor interactions. New derivatives do not show antioxidant activity (confirmed by the use of two different tests). A pKa assay method was developed to identify the basic physicochemical properties of 3e compound. A LogP assay confirmed that 3e compound fulfills Lipinsky's rule of five.

Keywords: Alzheimer’s disease; acetylcholinesterase inhibitors; beta amyloid; molecular modeling; yeast three-hybrid technology (Y3H) test.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Synthesis of compounds 2a–2h and 3a–3h. Reagents: (a) 6-chloronicotinic acid, CDMT, N-methylmorpholine, THF; (b) HCl/ether.
Figure 1
Figure 1
Reciprocal plots for EeAChE inhibition by compound 3e.
Figure 2
Figure 2
Scatterplots of mathematical formula results obtained for 3e compound with regression equation. The regression line is marked on the continuous line. Dashed lines determine the area of regression belt at the confidence level 0.95. (A) plot pH vs pH-log(Ax−Aa)/(Ab−Ax) 332/343 nm; (B) plot pH vs. pH-log(Ax−Aa)/(Ab−Ax) 343/332 nm; (C) plot pH vs. pH-log(Ax−Aa)/(Ab−Ax) 332/343 nm; (D) plot pH vs. pH-log(Ax−Aa)/(Ab−Ax) 343/332 nm.
Figure 3
Figure 3
Calibration curve for logP assay. The regression line is marked on the continuous line. Dashed lines determine the area of regression belt at the confidence level 0.95.
Figure 4
Figure 4
Binding mode of compound 3e with acetylcholinesterase (A) and butyrylcholinesterase (B).
Figure 5
Figure 5
Binding mode of compound 3g with acetylcholinesterase (A) and butyrylcholinesterase (B).
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