English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

Background  Malaria is one of the deadliest infectious diseases caused by protozoan parasite of  Plasmodium  spp. Increasing resistance to anti-malarials has become global threat in control of the disease and demands for novel anti-malarial interventions. Naturally-occurring coumarins, which belong to a class of benzo-α-pyrones, found in higher plants and some essential oils, exhibit therapeutic potential against various diseases. However, their limited uptake and non-specificity has restricted their wide spread use as potential drug candidates.    Methods  Two series of carbohydrate fused pyrano[3,2-c]pyranone carbohybrids which were synthesized by combination of 2- C -formyl galactal and 2- C -formyl glucal, with various freshly prepared 4-hydroxycoumarins were screened against  Plasmodium falciparum . The anti-malarial activity of these carbohybrids was determined by growth inhibition assay on  P. falciparum  3D7 strain using SYBR green based fluorescence assay. Haemolytic activity of carbohybrid  12 , which showed maximal anti-malarial activity, was determined by haemocompatibility assay. The uptake of the carbohybrid  12  by parasitized erythrocytes was determined using confocal microscopy. Growth progression assays were performed to determine the stage specific effect of carbohybrid  12  treatment on Pf3D7. In silico studies were conducted to explore the mechanism of action of carbohybrid  12  on parasite microtubule dynamics. These findings were further validated by immunofluorescence assay and drug combination assay.    Results  2-C-formyl galactal fused pyrano[3,2-c]pyranone carbohybrid  12  exhibited maximum growth inhibitory potential against  Plasmodium  with IC 50  value of 5.861 µM and no toxicity on HepG2 cells as well as no haemolysis of erythrocytes. An enhanced uptake of this carbohybrid compound was observed by parasitized erythrocytes as compared to uninfected erythrocytes. Further study revealed that carbohybrid  12  arrests the growth of parasite at trophozoite and schizonts stage during course of progression through asexual blood stages. Mechanistically, it was shown that the carbohybrid  12  binds to α,β-heterodimer of tubulin and affects microtubule dynamics.    Conclusion  These findings show carbohydrate group fusion to 4-hydroxycoumarin precursor resulted in pyrano-pyranones derivatives with better solubility, enhanced uptake and improved selectivity. This data confirms that, carbohydrate fused pyrano[3,2-c]pyranones carbohybrids are effective candidates for anti-malarial interventions against  P. falciparum .

malaria journal

Enhanced uptake, high selective and microtubule disrupting activity of carbohydrate fused pyrano-pyranones derived from natural coumarins attributes to its anti-malarial potential