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  • Tacrine an aminoacridine derivative Fig A was the

    2024-04-08

    Tacrine, an aminoacridine derivative (Fig. 1, A), was the first AChE inhibitor approved for treatment of AD [12], [13]. This compound was withdrawn from the market due to its hepatotoxicity [14]. In spite of tacrine's side effects, it is still an attractive lead compound for medicinal chemists due to its synthetic accessibility, low molecular weight and relatively easy modification [15]. To develop new less toxic tacrine derivatives with high anticholinesterase and selective peripheral binding potency, the replacement of benzene ring in the tacrine structure with different heterocyclic systems has been considered more extensively [16], [17]. Previously, we described a number of pyrazolo[4′,3′:5,6]pyrano[2,3-b]quinolines as novel tacrine-derived AChE inhibitors [18], [19]. Furthermore, Barreiro et al. have reported a series of tacrine-like compounds containing pyrazolo-quinoline scaffold (Fig. 1). The rat Betamethasone Dipropionate cholinesterases inhibition assay revealed that compound B (Fig. 1) had the most potent AChE inhibitory activity [20]. On the other hand, some phthalazinone derivatives were also synthesized and evaluated for their AChE and BuChE inhibitory activities [21], [22], [23], [24]. In the light of above-mentioned reports, we were encouraged to design and synthesize a novel series of tacrine-based compounds through replacement of the benzene ring in tacrine with pyrazolo[1,2-b]phthalazine scaffold (Fig. 1). Thus we describe here the synthesis, in vitro and in silico studies of compounds 7a-u as multifunctional agents for AD therapy.
    Chemistry The straightforward synthetic route to target compounds 7a-u was illustrated in Scheme 1. The key intermediates pyrazolo[1,2-b]phthalazines 5a-u was synthesized via multi-component reaction of phthalimide (1), hydrazine hydrate (2), malononitrile (3) and appropriate benzaldehyde derivative 4 in the presence of NiCl2.·6H2O as catalyst in refluxing ethanol [25]. The pyrazolo[1,2-b]phthalazines 5 underwent AlCl3-catalyzed Friedländer cyclization with cyclohexanone (6) to obtain final products 7a-u[26].
    Results and discussion
    Conclusion A multi-component reaction followed by Friedländer reaction were applied to prepare a novel tacrine analogs 7a-u bearing pyrazolo[1,2-b]phthalazines as selective anti-acetycholinesterase agents. The anti-AChE activity of the designed compounds was optimized through altering the pendent group on C-14 position of the pentacyclic skeleton. Most of compounds showed selective anti-AChE activity at sub-micromolar levels. The best result was obtained by 3-fluorophenyl in compound 7o with IC50 of 23 nM against AChE. This compound was 15 times more potent than tacrine against AChE. Besides compound 7o, the 2-methoxyphenyl derivative 7l with IC50 of 49 nM showed high potency against AChE. The promising compounds 7o and 7l were highly selective for AChE over BuChE, and significantly less toxic than reference drug tacrine. Since compound 7l showed less cytotoxic effect on HepG2 cells, thus this compound was selected for further studies. The biological results indicated that compound 7l had neuroprotective activity against H2O2-induced damage in PC12 cells at higher concentrations. Moreover, compound 7l was found to be an inhibitor of AChE-induced Aβ aggregation, which can also interfere with Aβ self-aggregation. The docking study of compound 7l with AChE enzyme revealed that the fused rings component of the molecule made π-π stacking with the aromatic amino acids at the peripheral anionic site of the enzyme (PAS). The straightforward synthesis, high potency and selectivity against AChE, inhibition of AChE-induced Aβ aggregation as well as Aβ self-aggregation, relatively low toxicity, along with significant neuroprotective effects of newly designed tacrine-like compounds 7a-u introduce them as attractive lead compounds towards discovery of effective disease-modifying drugs for AD therapy.
    Experimental
    Acknowledgments