2,3-Dihydro-1H-cyclopenta[b]quinoline Derivatives as Acetylcholinesterase Inhibitors—Synthesis, Radiolabeling and Biodistribution

Szymański, Paweł; Lázníčková, Alice; Lázníček, Milan; Bajda, Marek; Malawska, Barbara; Markowicz, Magdalena; Mikiciuk-Olasik, Elżbieta

doi:10.3390/ijms130810067

Cited by 27 publications

(23 citation statements)

References 48 publications

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“…However, it was more selective towards BChE (IC 50 = 0.0354 nM) over AChE [40]. Among the analogs 8 ( Figure 4, Table 1) reported as hybrids of tacrine and hydrazine nicotinate moiety by the same research group [41,42], the analog 8a was weaker eeAChE inhibitor (IC 50 = 308 nM) than the reference tacrine (IC 50 = 5.46 nM) and was selective towards esBChE (IC 50 = 0.65 nM) [41]. The other analog 8b, with longer alkyl spacer and smaller size of tricyclic ring compared to 8a, was stronger AChEI (IC 50 = 3.65 nM) than tacrine (IC 50 = 5.46 nM) with 4685 times selectivity towards AChE over BChE (IC 50 = 17100 nM) [42].…”

Section: Tacrine Analogsmentioning

confidence: 96%

The Structural Hybrids of Acetylcholinesterase Inhibitors in the Treatment of Alzheimer’s Disease: A Review

Saxena¹

2019

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Alzheimer's Disease (AD) is characterized by the loss of memory and learning ability in elderly patients affecting large population worldwide. The enzyme Acetylcholinesterase (AChE), (E.C.3.1.1.7) plays a major role in the hydrolysis of the released neurotransmitter acetylcholine. Most of the clinically used drugs to treat AD are Acetylcholinesterase Inhibitors (AChEIs). These drugs can provide symptomatic benefits only and suffer with loss of therapeutic potential with time. Therefore, there is an urgent need of novel cholinesterase inhibitors with wider therapeutic window for the treatment of AD. The strategies targeting the AChE enzyme along with other target(s) like Butyrylcholinesterase (BChE), amyloid-β (Aβ), β-secretase-1 (BACE), metals (Cu 2+ , Zn 2+ , or Fe 2+), antioxidant properties and free radical scavenging capacity have been mainly focused in the last five years. A number of hybrid molecules incorporating sub-structures with the desired well-established pharmacological profile into a single scaffold have been investigated. The main sub structures used in developing these molecules are derived from diverse chemical classes such as acridine, quinoline, carbamates, huperzine and other heterocyclic analogs. It has been followed by optimization of activity through structural modifications of the prototype molecules for developing the Structure Activity Relationship (SAR). This has led to the development of novel molecules with desired AChE inhibitory activity along with other desirable pharmacological properties. This review summarizes the current therapeutic strategies for the development of these AChEI in the last seven years.

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Section: Tacrine Analogsmentioning

confidence: 96%

The Structural Hybrids of Acetylcholinesterase Inhibitors in the Treatment of Alzheimer’s Disease: A Review

Saxena¹

2019

AND

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“…The final hydrochlorides, derivatives 19a–h , were obtained through crystallization from HCl in ether (Figure ). Quinoline compounds 21a–h were obtained by Szymański, Lázničková, Lázniček, et al () using the same method described above for tacrine analogs 19a–h (Figure ).…”

Section: Synthetic Modes Of Tacrine Derivativesmentioning

confidence: 99%

“…Synthesis of tacrine–hydrazinonicotinamide hybrids 19a–h , 8‐amino‐2,3‐dihydro‐1H‐cyclopenta[b]quinolones 20a–h and 6‐Hydrazino‐ N ‐[2‐(2,3‐dihydro‐1H‐cyclopenta[b] quinolin‐9‐ylamino)alkyl]nicotinamide hydrochlorides 21a–h (Szymański et al, ; Szymański, Markowicz, & Mikiciuk‐Olasik, ; Szymański, Lázničková, Lázniček, et al, )…”

Section: Synthetic Modes Of Tacrine Derivativesmentioning

confidence: 99%

Multifunctional properties of novel tacrine congeners: cholinesterase inhibition and cytotoxic activity

Sabolová¹,

Kristián

Kožurková

2018

J of Applied Toxicology

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This review describes the synthesis of a wide range of novel tetrahydroacridine derivatives (tiocyanates, selenocyanates, ureas, selenoureas, thioureas, isothioureas, disulfides, diselenides and several tacrine homo- and hetro-hybrids). These tacrine congeners exhibit significant anticholinesterase and cytotoxic properties and may therefore be of considerable potential for the development of new drugs for the treatment of Alzheimer's disease.

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“…Studies on biodistribution of tetrahydroacridine derivatives with similar structure showed that these compounds accumulate mainly in the rat's lungs and intestines [30]. A series of novel tetrahydroacridine and cyclopentaquinoline derivatives with fluorobenzoic acid moieties were synthesized and evaluated for their anticancer properties by our research team previously [13,31].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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A series of nine tetrahydroacridine derivatives with iodobenzoic moiety were synthesized and evaluated for their cytotoxic activity against cancer cell lines-A549 (human lung adenocarcinoma), HT-29 (human colorectal adenocarcinoma) and somatic cell line-EA.hy926 (human umbilical vein cell line). All compounds displayed high cytotoxicity activity against A549 (IC 50 59.12-14.87 µM) and HT-29 (IC 50 17.32-5.90 µM) cell lines, higher than control agents-etoposide and 5-fluorouracil. Structure-activity relationship showed that the position of iodine in the substituent in the para position and longer linker most strongly enhanced the cytotoxic effect. Among derivatives, 1i turned out to be the most cytotoxic and displayed IC 50 values of 14.87 µM against A549 and 5.90 µM against HT-29 cell lines. In hyaluronidase inhibition assay, all compounds presented anti-inflammatory activity, however, slightly lower than reference compound. ADMET prediction showed that almost all compounds had good pharmacokinetic profiles. 1b, 1c and 1f compounds turned out to act against chemoresistance in cisplatin-resistant 253J B-V cells. Compounds intercalated into DNA and inhibited cell cycle in G0/G1 phase-the strongest inhibition was observed for 1i in A549 and 1c in HT-29. Among compounds, the highest apoptotic effect in both cell lines was observed after treatment with 1i. Compounds caused DNA damage and H2AX phosphorylation, which was detected in A549 and HT-29 cells. All research confirmed anticancer properties of novel tetrahydroacridine derivatives and explained a few pathways of their mechanism of cytotoxic action.

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2,3-Dihydro-1H-cyclopenta[b]quinoline Derivatives as Acetylcholinesterase Inhibitors—Synthesis, Radiolabeling and Biodistribution

Cited by 27 publications

References 48 publications

The Structural Hybrids of Acetylcholinesterase Inhibitors in the Treatment of Alzheimer’s Disease: A Review

The Structural Hybrids of Acetylcholinesterase Inhibitors in the Treatment of Alzheimer’s Disease: A Review

Multifunctional properties of novel tacrine congeners: cholinesterase inhibition and cytotoxic activity

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

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