Novel <i>N</i>‐benzylpiperidine derivatives of 5‐arylisoxazole‐3‐carboxamides as anti‐Alzheimer's agents

Saeedi, Mina; Felegari, Peyman; Iraji, Aida; Hariri, Roshanak; Rastegari, Arezoo; Mirfazli, Seyedeh Sara; Firuzi, Omidreza; Mahdavi, Mohammad; Akbarzadeh, Tahmineh

doi:10.1002/ardp.202000258

Cited by 17 publications

(5 citation statements)

References 28 publications

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“…Compounds A-F (Fig. 2) are some AChE examples [53][54][55][56][57][58][59] . However, those inhibitors that possess a positive charge (quaternary amines) are mostly unable to cross the blood-brain barrier (BBB) and show poor efficiency in CNS.…”

Section: Resultsmentioning

confidence: 99%

Design, synthesis, in silico and biological evaluations of novel polysubstituted pyrroles as selective acetylcholinesterase inhibitors against Alzheimer’s disease

Pourtaher

Hasaninejad

Iraji

2022

Sci Rep

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The objective of this study was to design new polysubstituted pyrrole derivatives as selective acetylcholinesterase (AChE) inhibitors to target Alzheimer's disease. In this context, a highly efficient, one-pot, sequential, multi-component synthesis of a diverse range of polysubstituted pyrroles was developed through a sequential domino strategy by the condensation of amines with 1,1-bis(methylthio)-2-nitroethene (BMTNE), Knovenagle reaction of arylglyoxals with malono derivatives and subsequent Michael addition and intramolecular cyclization reaction in EtOH at reflux. Thirty-nine synthesized compounds were evaluated as AChE and butyrylcholinesterase (BChE) inhibitors. Among the synthesized compounds, compound 4ad (IC50 = 2.95 ± 1.31 µM) was the most potent and selective AChE inhibitor with no significant inhibition against butyrylcholinesterase BChE. A kinetic study of 4ad revealed that this compound inhibited AChE in an uncompetitive mode. Based on a molecular modeling study, compound 4ad due to its small size properly fitted into the active site of AChE compared to BChE and stabilized by H-bond and hydrophobic interactions with the critical residues of the AChE binding pocket. Consequently, it was proposed that the 4ad derivative can be an ideal lead candidate against AD with a simple and practical operation of synthetic procedures.

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Section: Resultsmentioning

confidence: 99%

Design, synthesis, in silico and biological evaluations of novel polysubstituted pyrroles as selective acetylcholinesterase inhibitors against Alzheimer’s disease

Pourtaher

Hasaninejad

Iraji

2022

Sci Rep

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“…All synthesized compounds were characterized by FTIR, 1 H-NMR, 13 C-NMR, elemental analysis, and HPLC ( Supplementary Information ). It should be noted that 1 H and 13 CNMR spectra of most compounds indicated the presence of two isomers probably due to restricted C-N amide bond rotation 41 . Also, the presence of two isomers was obvious in HPLC chromatograms.…”

Section: Resultsmentioning

confidence: 97%

Cyanoacetohydrazide linked to 1,2,3-triazole derivatives: a new class of α-glucosidase inhibitors

Iraji

Shareghi-Brojeni

Mojtabavi

et al. 2022

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In this work, a novel series of cyanoacetohydrazide linked to 1,2,3-triazoles (9a–n) were designed and synthesized to be evaluated for their anti-α-glucosidase activity, focusing on the fact that α-glucosidase inhibitors have played a significant role in the management of type 2 diabetes mellitus. All synthesized compounds except 9a exhibited excellent inhibitory potential, with IC50 values ranging from 1.00 ± 0.01 to 271.17 ± 0.30 μM when compared to the standard drug acarbose (IC50 = 754.1 ± 0.5 μM). The kinetic binding study indicated that the most active derivatives 9b (IC50 = 1.50 ± 0.01 μM) and 9e (IC50 = 1.00 ± 0.01 μM) behaved as the uncompetitive inhibitors of α-glucosidase with Ki = 0.43 and 0.24 μM, respectively. Moreover, fluorescence measurements were conducted to show conformational changes of the enzyme after binding of the most potent inhibitor (9e). Calculation of standard enthalpy (ΔHm°) and entropy (ΔSm°) values confirmed the construction of hydrophobic interactions between 9e and the enzyme. Also, docking studies indicated desired interactions with important residues of the enzyme which rationalized the in vitro results.

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“…Based on the in vitro results, compound 5 appears most potent inhibitor of AChE ( IC 50 = 16.07 μM) and BChE ( IC 50 = 15.16 μM) and exhibited selective anti-AChE activity ( IC 50 = 23.63 M). Thus, aryl isoxazole benzylpiperidine-based compounds could be considered potential agents for the treatment of AD [ 61 ]. A new class of multifunctional hybrids has been developed and tested by Piemontese et al that could be potential agents for AD.…”

Section: Donepezil-based Hybridsmentioning

confidence: 99%

Molecular Insights into Therapeutic Potentials of Hybrid Compounds Targeting Alzheimer’s Disease

et al. 2022

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Alzheimer’s disease (AD) is one of the most complex progressive neurological disorders involving degeneration of neuronal connections in brain cells leading to cell death. AD is predominantly detected among elder people (> 65 years), mostly diagnosed with the symptoms of memory loss and cognitive dysfunctions. The multifarious pathogenesis of AD comprises the accumulation of pathogenic proteins, decreased neurotransmission, oxidative stress, and neuroinflammation. The conventional therapeutic approaches are limited to symptomatic benefits and are ineffective against disease progression. In recent years, researchers have shown immense interest in the designing and fabrication of various novel therapeutics comprised of naturally isolated hybrid molecules. Hybrid therapeutic compounds are developed from the combination of pharmacophores isolated from bioactive moieties which specifically target and block various AD-associated pathogenic pathways. The method of designing hybrid molecules has numerous advantages over conventional multitarget drug development methods. In comparison to in silico high throughput screening, hybrid molecules generate quicker results and are also less expensive than fragment-based drug development. Designing hybrid-multitargeted therapeutic compounds is thus a prospective approach in developing an effective treatment for AD. Nevertheless, several issues must be addressed, and additional researches should be conducted to develop hybrid therapeutic compounds for clinical usage while keeping other off-target adverse effects in mind. In this review, we have summarized the recent progress on synthesis of hybrid compounds, their molecular mechanism, and therapeutic potential in AD. Using synoptic tables, figures, and schemes, the review presents therapeutic promise and potential for the development of many disease-modifying hybrids into next-generation medicines for AD.

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Novel N‐benzylpiperidine derivatives of 5‐arylisoxazole‐3‐carboxamides as anti‐Alzheimer's agents

Cited by 17 publications

References 28 publications

Design, synthesis, in silico and biological evaluations of novel polysubstituted pyrroles as selective acetylcholinesterase inhibitors against Alzheimer’s disease

Design, synthesis, in silico and biological evaluations of novel polysubstituted pyrroles as selective acetylcholinesterase inhibitors against Alzheimer’s disease

Cyanoacetohydrazide linked to 1,2,3-triazole derivatives: a new class of α-glucosidase inhibitors

Molecular Insights into Therapeutic Potentials of Hybrid Compounds Targeting Alzheimer’s Disease

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