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

Abstract

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 IC50 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.

Target-Based Virtual Screening of Natural Compounds Identifies a Potent Antimalarial With Selective Falcipain-2 Inhibitory Activity

“…To combat the problem of antimalarial resistance, there is a pressing need for development of new drug combinations that can target multiple pathways in malarial parasites. Here, we used the systematic approach to validate possible drug combinations of ST72 with known antimalarial chloroquine (CQ) ( Gupta et al, 2019 ). The effect of compounds alone or in combinations was assessed on the growth of parasite.…”

“…The plates were incubated for 72 hrs at 37°C. The parasitemia was determined by the SYBR Green method as described above ( Gupta et al, 2019 ). The combination index (CI).…”

Recent Advances in the Synthesis and Application of C-2-Formyl Glycals

“…Sagar, Singh, and co-workers 68 tested two series of carbohydrate-fused pyrano[3,2- c ]pyranone carbohybrids against Plasmodium falciparum . These hybrids were made by combining C -2-formyl galactal 6b and C -2-formyl glucal 6a with various freshly synthesized 4-hydroxycoumarins 35a – j (Scheme 11 ).…”

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

“…Please note, following publication of the original article [1], the authors have advised of three errors that are present in the published article. Firstly, the two instances of ' Albumax II' in the 'Methods' section of the article are incorrect: the reagent ' Albumax I' should be referred to instead.…”

“…Author details 1 Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India. 2 School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India.…”