Antiplasmodial activity of triterpenes isolated from the methanolic leaf extract of Combretum racemosum P. Beauv

Oluyemi, Wande M.; Samuel, Babatunde; Kaehlig, Hanspeter; Zehl, Martin; Parapini, Silvia; D’Alessandro, Sarah; Taramelli, Donatella; Krenn, Liselotte

doi:10.1016/j.jep.2019.112203

Cited by 15 publications

(14 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another triterpenoid, lupeol (47), isolated from methanol of Cassia siamea stem bark extract showed an IC 50 of 5 µg/mL against P. falciparum using a parasite lactate dehydrogenase (pLDH) assay (Ajaiyeoba et al, 2008). Phytochemical investigation of the methanolic leaf extract of Combretum racemosum led to the identification of ursane-type triterpenes, with the most active antiplasmodial compound being madecassic acid (48) with mean EC 50 ± SD values of 28 ± 12 and 17 ± 4 µg/mL against chloroquine-sensitive (D10) and chloroquine-resistant (W2) P. falciparum, respectively (Oluyemi et al, 2020).…”

Section: Terpenoidsmentioning

confidence: 99%

A Review of the Antimalarial, Antitrypanosomal, and Antileishmanial Activities of Natural Compounds Isolated From Nigerian Flora

et al. 2020

View full text Add to dashboard Cite

The West African country Nigeria features highly diverse vegetation and climatic conditions that range from rain forest bordering the Atlantic Ocean in the South to the Desert (Sahara) at the Northern extreme. Based on data from the World Conservation Monitoring Center of the United Nations Environmental Protection, Nigeria, with ~5,000 documented vascular plants, ranks amongst the top 50 countries in terms of biodiversity. Such a rich biodiversity implies that the country is rich in diverse secondary metabolites—natural products/unique chemicals produced by the plant kingdom to confer selective advantages to them. Like many tropical countries, Nigeria is also endemic to numerous infectious diseases particularly those caused by parasitic pathogens. These phytochemicals have been exploited for the treatment of diseases and as a result, a new branch of chemistry, natural product chemistry, has evolved, to try to reproduce and improve the therapeutic qualities of particular phytochemicals. In this review, we have compiled a compendium of natural products, isolated from Nigerian flora, that have been reported to be effective against certain protozoan parasites with the aim that it will stimulate interests for further investigations, and give impetus to the development of the natural products into registered drugs. In total 93 structurally characterized natural compounds have been identified with various levels of anti-parasite activity mainly from Nigerian plants. The synthesis protocol and molecular target for some of these natural anti-parasite agents have been established. For instance, the anti-plasmodial compound fagaronine (7), a benzophenanthridine alkaloid from Fagara zanthoxyloides has been successfully synthesized in the laboratory, and the anti-trypanosomal compound azaanthraquinone (55) elicits its effect by inhibiting mitochondrial electron transfer in trypanosomes. This review also discusses the barriers to developing approved drugs from phytochemicals, and the steps that should be taken in order to accelerate the development of new antiparasitics from the highlighted compounds.

show abstract

Section: Terpenoidsmentioning

confidence: 99%

A Review of the Antimalarial, Antitrypanosomal, and Antileishmanial Activities of Natural Compounds Isolated From Nigerian Flora

et al. 2020

View full text Add to dashboard Cite

show abstract

“…In our previous study, we isolated some potent antimalarial triterpenes from Combretum racemosum 20 and Combretum zenkeri 21 which further demonstrated the significance of the Combretaceae in the search for bioactive compounds useful in the treatment of malaria. In this study, we employed a computational approach which is a faster and cost-effective method for the identification of potential inhibitors of pfLDH from the bioactive compounds of Combretaceae species.…”

Section: Introductionmentioning

confidence: 79%

High-Throughput Virtual Screening with Molecular Docking, Pharmacophore Modelling and ADME Prediction to Discover Potential Inhibitors of Plasmodium falciparum Lactate Dehydrogenase (PfLDH) from Compounds of Combretaceae Family

2021

TJNPR

View full text Add to dashboard Cite

The increased prevalence of malaria requires continuous efforts towards the discovery of natural antimalarial agents targeting important biochemical pathways of the parasite. The Plasmoduim falciparum lactate dehydrogenase (pfLDH) is a glycolytic enzyme whose critical roles and unique characteristics make it an efficient antimalarial target. The aim of this study was to employ in silico methods to identify potential inhibitors of pfLDH from the selected bioactive compounds of Combretaceae species. One hundred and fifty (150) Combretaceae compounds were screened using molecular docking analysis on Schrödinger Maestro 12.5, followed by pharmacophore modelling and ADMET (absorption, distribution, metabolism, excretion and toxicity) study of the highest affinity compounds. Myricetin 3-O-glucoside and 2''-O-Galloylisovitexin showed higher binding affinities (-13.413 Kcal/mol and -12.896 Kcal/mol respectively) for pfLDH compared with -10.400 Kcal/mol displayed by nicotinamide adenine dinucleotide (NADH) (the co-factor). They interacted with GLY27, GLY29, MET30, ILE31, ASP53, GLY99, THR101 and TYR247 at the NADH binding site of the enzyme. The pharmacophore modelling showed the involvement of aromatic rings and hydrogen bond donors and acceptors in the interactions of the compounds with the target. Hence, these compounds could be said to possess the structural features, binding affinities and molecular interactions required as inhibitors of pfLDH and could be developed into antimalarial drugs following lead optimisation and experimental studies.

show abstract

“…The investigated triterpenes 19α‐hydroxyasiatic acid, arjungenin, 6β,23‐dihydroxytormentic acid, combregenin, terminolic acid and madecassic acid had been isolated in our previous work, [21] and they interacted with pf LDH with various levels of binding affinity. All six triterpenes occupied the binding sites of the co‐factor (NADH) and substrate (pyruvate) of pf LDH showing higher binding affinities than chloroquine.…”

Section: Resultsmentioning

confidence: 99%

“…Our recent work reported the isolation of antimalarial triterpenoids from a leaf extract of Combretum racemosum P. Beauv., with proven activity against chloroquine‐sensitive (D10) and chloroquine‐resistant (W2) strains of Plasmodium falciparum , and MA demonstrated the highest activity (IC 50 ; D10: 28±12 μg/mL, IC 50 ; W2: 17±4 μg/mL) compared to the others [21] . These include madecassic acid (MA), arjungenin (ARJ), 6β,23‐dihydroxytormentic acid (DHT), combregenin (CBG), terminolic acid (TA) and 19α‐hydroxyasiatic acid (HAA).…”

Section: Introductionmentioning

confidence: 99%

An Allosteric Inhibitory Potential of Triterpenes from Combretum racemosum on the Structural and Functional Dynamics of Plasmodium falciparum Lactate Dehydrogenase Binding Landscape

Oluyemi

Samuel

Adewumi

et al. 2022

Chemistry & Biodiversity

Self Cite

View full text Add to dashboard Cite

Multidrug resistance is a significant drawback in malaria treatment, and mutations in the active sites of the many critical antimalarial drug targets have remained challenging. Therefore, this has necessitated the global search for new drugs with new mechanisms of action. Plasmodium falciparum lactate dehydrogenase (pfLHD), a glycolytic enzyme, has emerged as a potential target for developing new drugs due to the parasite reliance on glycolysis for energy. Strong substrate‐binding is required in pfLDH enzymatic catalysis; however, there is a lack of information on small molecules’ inhibitory mechanism bound to the substrate‐binding pocket. Therefore, this study investigated a potential allosteric inhibition of pfLDH by targeting the substrate‐binding site. The structural and functional behaviour of madecassic acid (MA), the most promising among the six triterpenes bound to pfLDH, were unravelled using molecular dynamic simulations at 300 ns to gain insights into its mechanism of binding and inhibition and chloroquine as a standard drug. The docking studies identified that the substrate site has the preferred position for the compounds even in the absence of a co‐factor. The bound ligands showed comparably higher binding affinity at the substrate site than at the co‐factor site. Mechanistically, a characteristic loop implicated in the enzyme catalytic activity was identified at the substrate site. This loop accommodates key interacting residues (LYS174, MET175, LEU177 and LYS179) pivotal in the MA binding and inhibitory action. The MA‐bound pfLHD average RMSD (1.60 Å) relative to chloroquine‐bound pfLHD RMSD (2.00 Å) showed higher stability for the substrate pocket, explaining the higher binding affinity (−33.40 kcal/mol) observed in the energy calculations, indicating that MA exhibited profound inhibitory activity. The significant pfLDH loop conformational changes and the allostery substrate‐binding landscape suggested inhibiting the enzyme function, which provides an avenue for designing antimalarial compounds in the future studies of pfLDH protein as a target.

show abstract

Antiplasmodial activity of triterpenes isolated from the methanolic leaf extract of Combretum racemosum P. Beauv

Cited by 15 publications

References 36 publications

A Review of the Antimalarial, Antitrypanosomal, and Antileishmanial Activities of Natural Compounds Isolated From Nigerian Flora

A Review of the Antimalarial, Antitrypanosomal, and Antileishmanial Activities of Natural Compounds Isolated From Nigerian Flora

High-Throughput Virtual Screening with Molecular Docking, Pharmacophore Modelling and ADME Prediction to Discover Potential Inhibitors of Plasmodium falciparum Lactate Dehydrogenase (PfLDH) from Compounds of Combretaceae Family

An Allosteric Inhibitory Potential of Triterpenes from Combretum racemosum on the Structural and Functional Dynamics of Plasmodium falciparum Lactate Dehydrogenase Binding Landscape

Contact Info

Product

Resources

About