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Discovery of Helminthosporin, an Anthraquinone Isolated from Rumex abyssinicus Jacq as a Dual Cholinesterase Inhibitor.

ABSTRACT: Natural products have extensively contributed toward the discovery of new leads for Alzheimer's disease. During our search for new inhibitors of cholinesterase enzymes from natural sources, the ethyl acetate (EtOAc) extract of Rumex abyssinicus Jacq was identified as a dual cholinesterase inhibitor with IC50 values of 2.7 and 11.4 ?g/mL against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), respectively. The phytochemical investigation of the EtOAc extract has resulted in isolation of four anthraquinones, namely, helminthosporin, emodin, chrysophanol, and physcion, amongst which the helminthosporin has been isolated for the first time from Rumex sp. All isolated secondary metabolites have displayed significant inhibition of EeAChE with IC50 values of 2.63, 15.21, 33.7, and 12.16 ?M, respectively. In addition, the helminthosporin was also found to inhibit BChE with an IC50 value of 2.99 ?M. The enzyme kinetic study has indicated that helminthosporin inhibits AChE and BChE in a noncompetitive manner with k i values of 10.3 and 12.3 ?M, respectively. The results of molecular modeling and propidium iodide displacement assay have revealed that helminthosporin occupies the peripheral anionic site of the active site gorge of AChE. In the PAMPA-BBB permeability assay, helminthosporin was found to possess high BBB permeability (P e = 6.16 × 10-6 cm/s). In a nutshell, helminthosporin has been identified as a brain permeable dual cholinesterase inhibitor, and thus its further synthetic exploration is warranted for optimization of its potency.

SUBMITTER: Augustin N

PROVIDER: S-EPMC6990627 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Discovery of Helminthosporin, an Anthraquinone Isolated from Rumex abyssinicus Jacq as a Dual Cholinesterase Inhibitor.

Augustin Ntemafack N Nuthakki Vijay K VK Abdullaha Mohd M Hassan Qazi Parvaiz QP Gandhi Sumit G SG Bharate Sandip B SB

ACS omega 20200113 3

Natural products have extensively contributed toward the discovery of new leads for Alzheimer's disease. During our search for new inhibitors of cholinesterase enzymes from natural sources, the ethyl acetate (EtOAc) extract of Rumex abyssinicus Jacq was identified as a dual cholinesterase inhibitor with IC50 values of 2.7 and 11.4 μg/mL against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), respectively. The phytochemical investigation of the EtOAc extract has re ...[more]

PMID: 32010836

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Project description:BackgroundAntibiotic resistance has contributed to the burden of infectious diseases both in the hospital and community setting, and represents a great threat to public health. Previous studies have revealed the role of reactive oxygen species as intermediate mediators of tissue damage, following antibiotherapies, indicating the need of associating antioxidants to these treatments. Therefore, the present work was designed to study the antibacterial, antifungal and antioxidant activities of extracts and compounds from Rumex abyssinicus Jacq. (Polygonaceae), as well as to investigate the antibacterial mechanisms of action of the most effective agents.MethodsThe plant extracts were prepared by maceration in organic solvents followed by column chromatography of the EtOAc fraction and purification of different fractions which led to the isolation and characterization of pure compounds. The antimicrobial activities of the extracts/compounds and their combinations with ciprofloxacin and fluconazole were evaluated using the broth microdilution method by determining the minimum inhibitory concentration (MIC) and minimum microbicidal concentration (MMC). The effects of the extracts on the bacterial cell membrane and microbial respiratory chain dehydrogenase enzyme activity were determined by spectrophotometric methods. Antioxidant activity was evaluated using 1,1-diphenyl-2-picrylhydrazyl (DPPH) and gallic acid equivalent antioxidant capacity (GAEAC) assays.ResultsChrysophanol (1), physcion (2), Ergosta-6,22-diene-3,5,8-triol (3), emodin (4), 6-hydroxyemodin (citreorosein) (5), chrysophanein (6) and physcionin (7) were isolated from EtOAc fraction of R. abyssinicus and displayed different degrees of antimicrobial activities (MIC = 8-256 μg/mL). The MeOH extract and compounds 2 and 4 exhibited synergistic effects with ciprofloxacin and fluconazole. Compounds 1, 2 and the combined mixture of 6 + 7 displayed the highest antioxidant activity (GAEAC = 83.38-106.03 μg/mL).ConclusionR. abyssinicus is a potential source of antibacterial, antifungal and antioxidant agents. The antibacterial mechanisms of action of the MeOH extract and compound 2 are due to disruption of the cytoplasmic membrane and inhibition of the microbial respiratory chain dehydrogenase enzyme activity. To the best of our knowledge, this is the first report of test samples and ciprofloxacin / fluconazole association against MDR strains. The observed activity of the isolated compounds against bacteria and fungi including MDR strains deserves further exploration.

Project description:Cancer as a multistage process can be reversed or blocked by using chemopreventive agents. Colon cancer chemoprevention has been widely investigated using cyclooxygenase inhibitors and many other chemicals of synthetic or natural origin. This particular study was carried out to assess the colon cancer chemopreventive effect of hydro-methanol extract of Rumex abyssinicus rhizome on rats.Colon cancer chemopreventive potential of hydro-methanol extract of Rumex abyssinicus rhizome was determined based on the number and multiplicity of aberrant crypt foci (ACF). Fifteen DMH (1, 2-dimethylhydrazine) treated and five untreated Wistar female rats were used. DMH was administered subcutaneously 30 mg/kg, after its pH was adjusted to 6.5-7. Treatment groups started receiving extract after six weeks of weekly DMH injections. The rats were divided in to four groups: Group 1 received only oral normal saline, Group 2 received DMH and normal saline, Group 3 and 4 received DMH plus 250 mg/kg and 500 mg/kg extract, respectively. Specific phytoconstituents of the plant, which were reviewed from original articles, were virtually evaluated for cyclooxygenase-2 (COX-2) inhibition. The binding energies and interactions of the phytochemicals from Rumex abyssinicus against COX-2 were determined by Autodock4.2.There was a statistically significant reduction (p-value?<?0.05) in the number of aberrant crypt (AC) and aberrant crypt foci (ACF) at both administered doses. However, significant association (p-value?>?0.05) was not observed in reducing crypt multiplicity. The docking process resulted in estimated binding energies [-6.83 kcal/mol to -7.9 kcal/mol] which are closer to the positive controls or Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) [-4.55 kcal/mol to -10.84 kcal/mol]. The phytochemical-COX-2 interaction indicated the involvement of key amino acid residues in inhibition of cyclooxygenase like ARG120, TYR355, TYR385, SER530 and GLY526.Rumex abyssinicus had demonstrated a chemopreventive potential at post-initiation stage. As the virtual screening data suggested, COX-2 inhibition by the anthraquinones in the extract could be one mechanism for the observed chemopreventive effect.

Dataset Information

Discovery of Helminthosporin, an Anthraquinone Isolated from Rumex abyssinicus Jacq as a Dual Cholinesterase Inhibitor.

Publications

Discovery of Helminthosporin, an Anthraquinone Isolated from <i>Rumex abyssinicus</i> Jacq as a Dual Cholinesterase Inhibitor.

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