Synthesis, biological evaluation and molecular modeling of oxoisoaporphine and oxoaporphine derivatives as new dual inhibitors of acetylcholinesterase/butyrylcholinesterase

Tang, Huang; Wei, Yanping; Zhang, Chi; Ning, Fang-Xian; Qiao, Wei; Huang, Shi‐Liang; Ma, Lin; Huang, Zhi‐Shu; Gu, Lian‐Quan

doi:10.1016/j.ejmech.2009.01.021

Cited by 70 publications

(34 citation statements)

References 29 publications

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“…To confirm the results obtained by the Ellman's test, 1 H NMR experiments were also carried out 17 . The NMR method required a low concentration of enzyme (1.0 pM) in phosphate buffer at pH 7.4 and with the presence of 5% albumin to maintain the enzyme activity for a long time because EeAChE is a very fast enzyme in its hydrolysis of ACh.…”

Section: Assessment Of Inhibition Of Eeachementioning

confidence: 89%

Design, synthesis, and evaluation of guanylhydrazones as potential inhibitors or reactivators of acetylcholinesterase

Petronilho

Rennó

Castro

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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Analogs of pralidoxime, which is a commercial antidote for intoxication from neurotoxic organophosphorus compounds, were designed, synthesized, characterized, and tested as potential inhibitors or reactivators of acetylcholinesterase (AChE) using the Ellman's test, nuclear magnetic resonance, and molecular modeling. These analogs include 1-methylpyridine-2-carboxaldehyde hydrazone, 1-methylpyridine-2-carboxaldehyde guanylhydrazone, and six other guanylhydrazones obtained from different benzaldehydes. The results indicate that all compounds are weak AChE reactivators but relatively good AChE inhibitors. The most effective AChE inhibitor discovered was the guanylhydrazone derived from 2,4-dinitrobenzaldehyde and was compared with tacrine, displaying similar activity to this reference material. These results indicate that guanylhydrazones as well as future similar derivatives may function as drugs for the treatment of Alzheimer's disease.

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Section: Assessment Of Inhibition Of Eeachementioning

confidence: 89%

Design, synthesis, and evaluation of guanylhydrazones as potential inhibitors or reactivators of acetylcholinesterase

Petronilho

Rennó

Castro

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…In addition to MAOs, acetyl/butyryl cholinesterases have also been reported to be inhibited by oxoisoaporphines and oxoaporphines [29]. Unlike for MAO-A, an AChE has been reported to be present in the glycosome of T. evansi , which might act by regulating the flow of Ca +2 between the organelle and the cytosol [30].…”

Section: Discussionmentioning

confidence: 99%

Synthetic Oxoisoaporphine Alkaloids: In Vitro, In Vivo and In Silico Assessment of Antileishmanial Activities

et al. 2013

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Leishmaniasis is a growing health problem worldwide. As there are certain drawbacks with the drugs currently used to treat human leishmaniasis and resistance to these drugs is emerging, there is a need to develop novel antileishmanial compounds, among which isoquinoline alkaloids are promising candidates. In this study, 18 novel oxoisoaporphine derivatives were synthesized and their possible antileishmanial activity was evaluated. The in vitro activity of these derivatives against Leishmania amazonensis axenic amastigotes was first evaluated, and the selected compounds were then tested in an inhibition assay with promastigotes of L. infantum, L. braziliensis, L. amazonensis and L. guyanensis, and with intracellular amastigotes of L. infantum and L. amazonensis. Finally, the most active compounds, OXO 1 (2,3-dihydro-7H-dibenzo[de,h]quinolin-7-one) and OXO 13 (2,3,8,9,10,11-hexahydro-7H-dibenzo[de,h]quinolin-7-one), were tested in BALB/c mice infected with L. infantum. Treatment of mice at a dose of 10 mg/kg with OXO 1 yielded significant reductions (p<0.05) in parasite burden in liver and spleen (99% and 78%, respectively) whereas with OXO 13 were not significant. Although previous reports suggest that this family of molecules displays inhibitory activity against monoamine oxidase A and acetylcholinesterase, these enzymes were not confirmed as targets for antileishmanial activity on the basis of the present results. However, after development of a new bioinformatics model to analyze the Leishmania proteome, we were able to identify other putative targets for these molecules. The most promising candidates were four proteins: two putative pteridine reductase 2 (1MXF and 1MXH), one N-myristoyltransferase (2WUU) and one type I topoisomerase (2B9S).

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“…1, 2 In the realm of central nervous system (CNS) activity, members of the aporphine class are known to inhibit the enzyme acetylcholinesterase - an important therapeutic target in current treatment modalities for Alzheimers disease. 3-5 Behavioral and physiological effects of the designer drug MDMA (“Ecstasy”, 1 ) are antagonized by nantenine ( 2 ), an isolate of a number of Lauraceous plants. With regards to clinically available aporphine drugs, apomorphine ( 3 ) is a potent dopamine D1/D2 agonist that is used to treat symptoms of Parkinson’s disease.…”

Section: Introductionmentioning

confidence: 99%

New aporphinoid 5-HT2A and α1A antagonists via structural manipulations of nantenine

Chaudhary¹,

Ponnala²,

LeGendre³

et al. 2011

Bioorganic & Medicinal Chemistry

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A series of C1, C2, C3 and N6 analogs of nantenine (2) was synthesized and evaluated in 5-HT2A and α1A receptor functional assays. Alkyl substitution of the C1 and N6 methyl groups of nantenine provided selective 5-HT2A and α1A antagonists respectively. The C2 alkyloxy analogs studied were generally selective for α1A vs 5-HT2A. The C3 bromo analog 15 is one of the most potent aporphinoid 5-HT2A antagonists known presently.

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Synthesis, biological evaluation and molecular modeling of oxoisoaporphine and oxoaporphine derivatives as new dual inhibitors of acetylcholinesterase/butyrylcholinesterase

Cited by 70 publications

References 29 publications

Design, synthesis, and evaluation of guanylhydrazones as potential inhibitors or reactivators of acetylcholinesterase

Design, synthesis, and evaluation of guanylhydrazones as potential inhibitors or reactivators of acetylcholinesterase

Synthetic Oxoisoaporphine Alkaloids: In Vitro, In Vivo and In Silico Assessment of Antileishmanial Activities

New aporphinoid 5-HT2A and α1A antagonists via structural manipulations of nantenine

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