Antimalarial Effects Research Articles

A Review on the Cytotoxic and Antimicrobial Properties of Xanthones from Cratoxylum cochinchinense

Cratoxylum cochinchinenseis a perennial plant found in Southeast Asia, having di-verse terminologies in various Southeast Asian countries. It has been traditionally used as medicine, tea and food spice until today. Its phytochemical analysis reveals a rich array of bioactive compounds in different parts of the plant, specifically xan-thones, which are scientifically determined to be the most abundant secondary me-tabolites in C. cochinchinense. Xanthones do possess numerous beneficial properties and are actively researched to unlock its vast potential. It could be synthesized both biologically and synthetically, where the latter method is gaining much interest among researchers to improve its biological properties. Due to limited compiled re-sources on the biological benefits of xanthones from C. cochinchinense, this paper aims to review theircytotoxic properties specifically towards cancer cells, as well as their antimalarial and antibacterial effects in order to further support the medicinal use of this plan

Alstonia scholaris Linn. R. Br.: An Assessment of its Botany, Conventional Utilizaton, Phytochemistry and Pharmacology

Alstonia scholaris, a plant that belongs to the Apocynaceae family and is widely used around the world, exhibits pharmacological properties that are advantageous to human health. It is a widely used plant that has been used in traditional medicine for a very long time. Rheumatism, antileprosy, ulcer, antiseptics, different chronic inflammatory skin conditions, rheumatoid arthritis discomfort, broad-spectrum tonic, antidysentery, and vulnerary agents have all been successfully treated with A. scholaris. Along with treating fatigue, antipyretic, anticholeric, malaria fever, irregular and unbalanced menstruation, hepatic problems, diabetes, and dysentery, it has also been beneficial in treating these other conditions. It possesses astringent, analgesic, anti-inflammatory, and anti-diabetic effects. Additionally, it has cytotoxic, radioprotective CNS, anti-arthritic, anti-cancer, antioxidant, anti-malarial, and anti-cancer effects. The numerous derivative metabolites were taken into account in the pioneering research on phytochemical analysis from the various plant sections. The plant displayed an abundance of metabolites, including tocopherols, polyunsaturated fatty acids, carboxylic acids, proteins, and carbohydrates. With a variety of biological functions, it also shown pharmaceutical efficacy. This evaluation seeks to acquaint the reader with the plant by adding to a clear overview of the botanical distinctiveness, typical uses, phytochemistry, and biological and pharmacological activities.

Isolation and Characterization of Prophylactic Antimalarial Agents from Ochna kibbiensis Leaves

Ochna kibbiensis (Family: Ochnaceae) has been employed in ethnomedicine for the treatment of malaria and inflammation, among others. The aim of this study was to isolate and characterize prophylactic antimalarial agents from the leaves of O. kibbiensis against Plasmodium berghei, in vivo and in silico. The median lethal dose (LD50) of the methanol extract and its fractions (hexane, dichloromethane, ethylacetate and butanol) was determined according to Lorke’s method while the antimalarial effect of the extract and its fractions was investigated according to the method described by Peters prophylactic test using Chloroquine-sensitive Plasmodium berghei (NK65). All the extract/fractions exhibited LD50 values ≥ 5000 mg/kg with the exception of the n-butanol fraction (1702.94 mg/kg), which indicate that the plant is non-toxic. Dichloromethane fraction exhibited a significant (p < 0.05) and dose-dependent prophylactic effect with 47.62, 85.12, and 100.0% prophylaxis (at 500, 250, and 125 mg/kg), while the least effect was observed by the butanol fraction with a percentage prophylaxis of 64.29 and 76.19, respectively; the standard drug, pyrimethamine, had 95.24% prophylaxis. Based on the results obtained, dichloromethane fraction of O. kibbiensis was subjected to chromatographic purification, which led to the isolation of a mixture of two compounds identified as stigmasterol and β-sitosterol by analysis of the NMR spectral data and comparison with existing literature; the compounds exhibited good binding affinities (−5.129 and −4.889 kcal/mol) against pfLDH and a favorable ADMET profile. In conclusion, the leaves of O. kibbiensis have demonstrated a significant prophylactic antimalarial activity and the two known steroids (stigmasterol and β-sitosterol) were isolated from the dichloromethane fraction for the first time.

Synergistic antimalarial treatment of Plasmodium berghei infection in mice with dihydroartemisinin and Gymnema inodorum leaf extract

BackgroundChemotherapy is crucial in the fight against malaria. The rise of resistance to most antimalarial medicines has been a serious hurdle to effective treatment. Artemisinin-based combination therapies (ACTs) are currently the most effective antimalarial medication. Malaria parasites are growing more resistant to ACTs, particularly in Southeast Asia. As a result, effective alternative antimalarials are in high demand. The leaf extract of Gymnema inodorum (GIE) has previously shown promise as an effective antimalarial. Therefore, this study evaluated the antimalarial potential of combination dihydroartemisinin (DHA) and GIE therapy against Plasmodium berghei in a mouse model.MethodsThe medications were evaluated using the standard 4-day test for determining the 50% effective dosage (ED50) of DHA and GIE on P. berghei ANKA (PbANKA). DHA and GIE were combined using a fixed-ratio approach, with DHA/GIE ED50s of 100/0, 80/20, 60/40, 40/60, 20/80, and 0/100, respectively.ResultsThe ED50 against PbANKA was determined to be 2 mg/kg of DHA and 100 mg/kg of GIE. The 60/40 (DHA/GIE) ratio demonstrated significantly higher antimalarial activity than the other ratios (p < 0.001) against PbANKA, with 88.95% inhibition, suggesting synergistic efficacy (combination index (CI) = 0.68695). Furthermore, this ratio protected PbANKA-infected mice against loss of body weight and packed cell volume decline, leading to a longer survival time over 30 days.ConclusionOur results suggest that GIE could be an effective adjuvant to DHA that can enhance the antimalarial effects in the treatment of PbANKA-infected mice.

Baseline prevalence of molecular marker of sulfadoxine/pyrimethamine resistance in Ebonyi and Osun states, Nigeria: amplicon deep sequencing of dhps-540.

Chemoprevention plays an important role in malaria control strategy. Perennial malaria chemoprevention (PMC) using sulfadoxine/pyrimethamine (SP) is a WHO-approved strategy to combat malaria in young children and may lead to drug pressure. Introducing SP-PMC may therefore be compromised due to the emergence of Plasmodium falciparum resistant to SP, particularly mutation at K540E of the dihydropteroate synthase (dhps) gene. Molecular surveillance of resistance markers can support assessment of antimalarial efficacy and effectiveness. High prevalence of 540E is associated with reduced effectiveness of SP, and areas with more than 50% prevalence are considered unsuitable for intermittent preventative treatment in pregnancy (IPTp) implementation. Assessing 540E prevalence is an important undertaking before implementation of SP-PMC. We conducted a rapid surveillance of dhps-540E to assess the suitability of SP as PMC in field studies from Ebonyi and Osun states in Nigeria. We used an in-house developed amplicon deep-sequencing method targeting part of the dhps gene. Our data reveal that 18.56% of individuals evaluated carried the 540E mutation mixed with the WT K540. Mutant variant 540E alone was not found, and 80% of isolates harboured only WT (K540). Clonal analysis of the sequencing data shows a very low proportion of 540E circulating in both states. Our data show that both states are suitable for SP-PMC implementation and, based on this finding, SP-PMC was implemented in Osun in 2022. Continuous monitoring of 540E will be required to ensure the chemoprevention effectiveness of SP in Nigeria.

Anti-Plasmodial Effects of Different Ecotypes of Glycyrrhiza glabra Traditionally Used for Malaria in Iran.

The online version contains supplementary material available at 10.1007/s43450-022-00353-8.

Quercetin nano phytosome: as a novel anti-leishmania and anti-malarial natural product.

Leishmaniasis is a vector-borne disease that affects several populations worldwide with the clinical manifestations in skin, mucous membranes, and internal organs and there are not any effective and available vaccines and conventional treatments are highly toxic. Quercetin is a kind of flavonoid with different biological effects including free radical scavenging and anti-microbial activity and this study is aimed to assess the anti-leishmania and anti-malarial effects of quercetin loaded phytosome and quercetin alone. In this experimental study, the in vitro activity of above drugs were measured using microscopically examinations and for evaluation the anti-leishmanial efficacy, the size of lesions were measured. Moreover the cytotoxicity of the treatments was evaluated on WI38 and J774 cell lines. Our results indicated that quercetin loaded phytosome and quercetin alone have acceptable anti-parasitic activity mostly at concentration of 400µg/ml on both P. falciparium and L. major. The results of cytotoxicity revealed that the mentioned drugs have no effects on human cell lines and also have no hemolytic activity. The drug of choice for the treatment of leishmaniasis, in addition to killing the parasite, should not have a toxic effect on human cells and our results indicated that quercetin can be a valuable candidate for treatment of different kinds of leishmaniasis.

Chalcone Mannich base derivatives: synthesis, antimalarial activities against Plasmodium knowlesi, and molecular docking analysis

Research on the antimalarial effect of aminoalkyl chalcone derivatives against Plasmodium falciparum and Plasmodium knowlesi has bolstered efforts in drug discovery to combat cases of drug resistance.

In vivo antiplasmodial activities of stem bark extracts of Avicennia marina in Plasmodium berghei-infected mice

malaria remains the leading cause of morbidity and mortality in developing tropical and subtropical nations. Due to the emergence and spread of drug resistance to currently available drugs, there is a need for the search of novel, safe, and reasonably affordable anti-malarial medications. The objective of this study was to assess the in vivoanti-malarial effectiveness of Avicennia marina stem bark extracts in a mice model. guidelines 425 of the Organization for Economic Cooperation and Development were used to determine the extracts' acute toxicity. Mice infected with chloroquine-sensitive Plasmodium berghei (ANKA strain) were tested for in vivoanti-plasmodial activity, and by giving oral doses of 100 mg/kg, 250 mg/kg, and 500 mg/kg body weight of extracts, the plant's suppressive, curative, and preventive effects were assessed. mice treated with dosages of up to 5000 mg/kg showed no evidence of acute toxicity or mortality. Consequently, it was determined that the acute lethal dosage of Avicennia marina extracts in swiss albino mice was greater than 5000 mg/kg. All doses of the extracts exhibited significant (p<0.05) dose-dependent suppression of P. berghei in the suppressive tests compared to the control group. At the highest dose (500 mg/kg), Methanolic crude extracts exerted the highest (93%) parasitemia suppression during the 4-day suppressive test. The extracts also displayed significant (p<0.001) prophylactic and curative activities at all doses compared to the control. results from this study ascertained the safety and promising curative, prophylactic and suppressive anti-plasmodial capabilities of the stem bark extracts of Avicennia marina in mice model.

SESN2 Knockdown Increases Betulinic Acid-Induced Radiosensitivity of Hypoxic Breast Cancer Cells

Betulinic acid (BA) is a natural compound well known for its anti-inflammatory, anti-viral, anti-bacterial, anti-malarial effects and anti-tumor properties. Its enhanced cytotoxicity in tumor cells and induction of cell death in various cancer entities qualifies BA as an interesting candidate for novel treatment concepts. Our analyses showed enhanced cytotoxicity and radiosensitization under hypoxic conditions in human breast cancer cells. So far, the underlying mechanisms are unknown. Therefore, we investigated the BA-treated human breast cancer cell lines MDA-MB-231 and MCF-7 under normoxic and hypoxic conditions based on microarray technology. Hypoxia and BA regulated a variety of genes in both breast cancer cell lines. KEGG pathway analysis identified an enrichment of the p53 pathway in MCF-7 cells (wtp53) under hypoxia. In MDA-MB-231 cells (mtp53) an additional BA incubation was required to activate the p53 signaling pathway. Fourteen down-regulated and up-regulated genes of the p53 pathway were selected for further validation via qRT-PCR in a panel of five breast cancer cell lines. The stress-induced gene Sestrin-2 (SESN2) was identified as one of the most strongly up-regulated genes after BA treatment. Knockdown of SESN2 enhanced BA-induced ROS production, DNA damage, radiosensitivity and reduced autophagy in breast cancer cells. Our results identified SESN2 as an important target to enhance the radiobiological and anti-tumor effects of BA on breast cancer cells.

The Potential of Plants of Family Fabaceaewith Emphasis on Putri Malu Medicinal Plant ‘Mimosa Pudica’ (Fabaceae) as an Antimalarial &amp; an Insecticide for Malaria Vectors: A Review

Background: Due to the prevalence of malaria worldwide and cases of resistance to malaria drugs, finding new drug candidates is important in malaria control. Due to its traditional use and phytochemical content, this review was conducted on the medicinal plant Mimosa pudica and its family, Fabaceae. Method: This review collected original articles in online databases using several keywords combined with boolean operators. The articles about the antimalarial and insecticidal effects of Mimosa pudica and other Fabaceae species were included in the study. Results: Forty-two articles described 45 species from the Fabaceaefamily exhibiting antimalarial and/ or insecticidal potential including Mimosa pudica. The studies showed that crude extract of M. pudica showed activity against P. falciparum or P. berghei and insecticidal activity against Anopheles subpictus and Anopheles stephensi. More advanced studies were carried out on other Fabaceae species, evaluating their activity with crude extracts and fractions, isolated compounds, and silver nanoparticles (AgNPs). Conclusions: The most promising antiplasmodial activity of M. pudica was shown by aqueous, methanol, and water/ methanol extracts from the aerial part against P. falciparum FCR-3 strain. In addition, aqueous or ethanolic extracts from the leaves of M. pudica revealed their potential against A. subpictus and A. stephensi.

Identification, in-vitro anti-plasmodial assessment and docking studies of series of tetrahydrobenzothieno[2,3-d]pyrimidine-acetamide molecular hybrids as potential antimalarial agents

Malaria is the most lethal parasitic infections in the world. To address the emergence of drug resistance to current antimalarials, here we report the design and synthesis of new series of tetrahydrobenzothieno[2,3-d]pyrimidine-acetamide hybrids by using multicomponent Petasis reaction as the key step and evaluated in vitro for their antimalarial effectiveness. The structure of all the compounds were confirmed by NMR Spectroscopy and mass spectrometry. Most of the compounds showed potent antimalarial activity against both CQ-sensitive (3D7) and CQ-resistant (W2) strains. A8, A5, and A4 are the most potent compounds that showed excellent anti-plasmodial activity against CQ-resistant strain in the nanomolar range with IC50 values 55.7 nM, 60.8 nM, and 68.0 nM respectively. To assess the parasite selectivity, the in vitro cytotoxicity of selected compounds (A3-A6, A8) was tested against HPL1D cells, demonstrating low cytotoxicity with high selectivity indices. Furthermore, these compounds were also evaluated on two additional human cancerous cell lines (A549 and MDA-MB-231), confirming their anticancer effectiveness. The in vitro hemolysis assay also showed the non-toxicity of these compounds on normal uninfected human RBCs. The interaction of these hybrids was also investigated by the molecular docking studies in the binding site of wild type Pf-DHFR-TS and quadruple mutant Pf-DHFR-TS. The in silico ADMET profiling also revealed promising physicochemical and pharmacokinetic parameters for the most active hybrids, which provide strong vision for further development of potential antimalarials.

Assessment of toxicity and anti-plasmodial activities of chloroform fractions of Carapa procera and Alchornea cordifolia in murine models.

Background: Plant as a source of medicine has gained international popularity in recent times because of its natural origin, availability in local communities, cheaper to purchase, ease of administration, and its usefulness as an alternative treatment in case of numerous side effects and drug resistance. However, the use of herbal formulations can also result in short-term and long-term organ damage or dysfunction to the host. In this study, chloroform fractions of the leaves of two medicinal plants, Alchornea cordifolia (ACL) and Carapa procera (CPL), were investigated for their toxicological and anti-malarial effects in murine models. Method: Acute (14-day) and sub-acute (28-day) studies were conducted based on the Organization for Economic Cooperation and Development (OECD) Guidelines in Institute for Cancer Research (ICR) mice and Sprague Dawley (SD) rats respectively. A dosage of 2000mg/kg body weight was administered orally to each ICR mouse during the acute study and 100, 300, and 1000mg/kg body weight to each SD rat during the sub-acute study. A 5-day curative anti-plasmodial activity was assessed in ICR mouse model. Results: The assessment of toxicity revealed that all three fractions did not influence mortality, clinical appearance, body weight gain, or necropsy at the various doses. Hematological and serum biochemical analysis indicated no significant elevations in liver and renal function parameters. Histopathological examinations of the liver indicated reversible liver degeneration with the chloroform fraction of the 100% ethanol extract of Carapa procera leaves (CPL100%) at 1000mg/kg. Anti-plasmodial assessments showed CPL100% exhibiting dose-dependent anti-plasmodial activity from 16% to 26.67%. On the other hand, chloroform fraction of the 100% ethanol extract of Alchornea cordifolia leaves (ACL100%) showed declining anti-plasmodial activity from 21.1% to 15.1%. Conclusion: These preliminary findings demonstrate that chloroform fractions of the leaves of Carapa procera and Alchornea cordifolia may be safe agents for treating malaria hence further development for drug discovery must be pursued.

A Postulated Mechanism of the Antimalarial Effect of Free Radicals Generated by Artemisinin on Plasmodium falciparum

Artemisinin and its derivatives, a class of antimalarial drugs, were first isolated from Artemisia annua. Artemisinin can alter the pH of the malaria parasite’s digestive vacuole from acidic to alkaline, leading to parasite death. However, the precise mechanism of artemisinin action in changing the digestive vacuole pH has not yet been confirmed. Previous studies reported that artemisinin and its derivatives could kill the parasites through the generation of oxidative stress by the free radicals they generate. This review aims to provide a better understanding of the possible mechanism of action of artemisinin, focusing on the antimalarial activity caused by the generated free radicals through the induction of mutation in the genes that encode the proton pump of the Plasmodium falciparum digestive vacuole.

Artemisinin Alleviates Cerebral Ischemia/Reperfusion-Induced Oxidative Damage via Regulating PHB2-Mediated Autophagy in the Human Neuroblastoma SH-SY5Y Cell Line.

Oxidative stress plays a key role in cerebral ischemia/reperfusion injury. Artemisinin (ART) has antioxidative stress activity in addition to its powerful antimalarial effects. In this article, we investigated the effect of ART on OGD/R-induced oxidative stress injury and its underlying mechanisms. We used oxygen-glucose deprivation/reoxygenation (OGD/R) to establish an in vitro model of cerebral ischemia/reperfusion (I/R) injury. CCK-8 and lactate dehydrogenase (LDH) release were used to assess cellular damage. Measurement of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and mitochondrial membrane potential (MMP) estimates oxidative stress-induced damage and protection from ART effect. OGD/R treatment aggravated oxidative stress damage, whereas ART reversed the effects of OGD/R. Autophagy is closely related to oxidative stress; in order to confirm whether the antioxidative stress effect of ART is related to PHB2-mediated autophagy, we examined the protein expression of prohibitin 2 (PHB2), TOMM20, p62, and the conversion of microtubule-associated protein light chain 3I (LC3I) to LC3II and found that the protein expression of PHB2, TOMM20, p62, and LC3II/LC3I was significantly correlated with OGD/R treatment. The colocalization of PHB2 and LC3, TOMM20, and LC3 was reduced after OGD/R treatment, and ART reversed this change. After silencing PHB2, the protective effect of ART against OGD/R-induced oxidative stress injury was reduced, the protein expressions of PHB2, TOMM20 and LC3II/LC3I and the colocalization of PHB2 and LC3, TOMM20, and LC3 were decreased. We used chloroquine to block the lysosomal pathway and found that ART increased the conversion of LC3I to LC3II, silencing PHB2 which inhibited the conversion of LC3I to LC3II, and impaired mitophagy. Our findings showed that ART attenuated OGD/R-induced oxidative stress damage through PHB2-mediated mitophagy. To the current knowledge, our study is the first to demonstrate that ART attenuates OGD/R-induced oxidative stress injury through PHB2-mediated autophagy in the human neuroblastoma SH-SY5Y cell line, which provided new insights into the treatment of OGD/R injury.

Antimalarial and immunomodulatory potential of chalcone derivatives in experimental model of malaria

BackgroundMalaria is a complex issue due to the availability of few therapies and chemical families against Plasmodium and mosquitoes. There is increasing resistance to various drugs and insecticides in Plasmodium and in the vector. Additionally, human behaviors are responsible for promoting resistance as well as increasing the risk of exposure to infections. Chalcones and their derivatives have been widely explored for their antimalarial effects. In this context, new derivatives of chalcones have been evaluated for their antimalarial efficacy.MethodsBALB/c mice were infected with P. berghei NK-65. The efficacy of the three most potent chalcone derivations (1, 2, and 3) identified after an in vitro compound screening test was tested. The selected doses of 10 mg/kg, 20 mg/kg, and 10 mg/kg were studied by evaluating parasitemia, changes in temperature, body weights, organ weights, histopathological features, nitric oxide, cytokines, and ICAM-1 expression. Also, localization of parasites inside the two vital tissues involved during malaria infections was done through a transmission electron microscope.ResultsAll three chalcone derivative treated groups showed significant (p < 0.001) reductions in parasitemia levels on the fifth and eighth days of post-infection compared to the infected control. These derivatives were found to modulate the immune response in a P. berghei infected malaria mouse model with a significant reduction in IL-12 levels.ConclusionsThe present study indicates the potential inhibitory and immunomodulatory actions of chalcones against the rodent malarial parasite P. berghei.

Preliminary Phytochemical Analysis and Invitro Antiplasmodial Activity of Terminalia mantaly Against Plasmodium falciparum

Highlights: Malaria is prevalent in many populations of communities despite preventive measures. The experimental was screened for bioactive components which could be the reason for the antimalarial effect and the plant shows dose dependent antimalarial activity. Abstract : Malaria has been one of the world’s worst killer diseases throughout recorded human history. Despite attempts to eradicate the disease, it remains a global burden. This could be a result of parasite resistance to current therapy. However, this research aimed at evaluating the in vitro antimalarial activity of ethanolic extracts of Terminalia mantaly on Plasmodium falciparum. The plant extracts were prepared by cold maceration in 70% ethanol and air-dried by a rotary evaporator. The phytochemical analysis was carried out using standard procedures outlined in the Analytical methods of the Association of Official Analytical Chemists (AOAC, 1990) which indicates the presence of tannins, alkaloids, saponins, flavonoids, glycosides, phenol, steroids, and balsam. The in vitro antimalarial assay was carried out according to the method described by WHO (2001). All data were represented as Mean ± Standard deviation. Ethanolic extracts of the three parts of the plant were subjected to in vitro antimalarial activity at three concentrations (300 mg, 150 mg, and 75 mg) in four replicates with artemether (standard drug) as a positive control. Stem bark at 300 mg/kg completely cleared the parasites with a 0.00% parasitaemia rate and there was no significant difference when compared with positive control at p&lt;0.005 value of 1.00. This study affirms the use of the plant for the treatment of malaria.

Artesunate inhibits osteoclast differentiation by inducing ferroptosis and prevents iron overload-induced bone loss.

Artemisinin compounds have been demonstrated to have anti-osteoporosis effects by inhibiting bone resorption. During osteoclast differentiation, osteoclasts take up a large amount of iron through transferrin receptor 1 (TfR1) mediated endocytosis of transferrin (Tf). Since iron-dependent cleavage of endoperoxide bridge is of great importance for the antimalarial effects of artemisinin compounds, we raised a hypothesis that the cytotoxic effects of artemisinin compounds on osteoclasts were associated with enhanced iron uptake. In the present study, we found that Tf aggravated the inhibitory effects of artesunate (ART) on osteoclast viability and differentiation. ART induced the production of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) in a dose-dependent manner and led to the appearance of mitochondrial features of ferroptotic cells. TfR1 knockdown alleviated these cytotoxic effects of ART on osteoclasts. In addition, ART effectively prevented bone loss induced by iron overload. Our results indicate that ART inhibits iron-uptake stimulated osteoclast differentiation by inducing ferroptosis. Artemisinin compounds are potential drugs for treating iron overload-induced osteoporosis.

Synthesis Strategies and Medicinal Value of Pyrrole and its Fused Heterocyclic Compounds.

In the last several decades, interest in pyrrole and pyrrolopyrimidine derivatives has increased owing to their biological importance, such as anti-tumor, anti-microbial, anti-inflammatory, anti-diabetic, anti-histaminic, anti-malarial, anti-Parkinson, antioxidant and anti-viral effects, specially recently against COVID-19. These tremendous biological features have motivated scientists to discover more pyrrole and fused pyrrole derivatives, owing to the great importance of the pyrrole nucleus as a pharmacophore in many drugs, and motivated us to present this article, highlighting on the different synthetic pathways of pyrrole and its fused compounds, specially pyrrolopyrimidine, as well as their medicinal value from 2017 till 2021.

Isoprenoid alcohols utilization by malaria parasites.

Plasmodium falciparum is the etiological agent of human malaria, one of the most widespread diseases in tropical and subtropical regions. Drug resistance is one of the biggest problems in controlling the disease, which leads to the need to discover new antimalarial compounds. One of the most promissory drugs purposed is fosmidomycin, an inhibitor of the biosynthesis of isoprene units by the methylerythritol 4-phosphate (MEP) pathway, which in some cases failed in clinical studies. Once formed, isoprene units are condensed to form longer structures such as farnesyl and geranylgeranyl pyrophosphate, which are necessary for Heme O and A formation, ubiquinone, and dolichyl phosphate biosynthesis as well as for protein isoprenylation. Even though the natural substrates of polyprenyl transferases and synthases are polyprenyl pyrophosphates, it was already demonstrated that isoprenoid alcohols (polyprenols) such as farnesol (FOH) and geranylgeraniol (GGOH) can rescue parasites from fosmidomycin. This study better investigated how this rescue phenomenon occurs by performing drug-rescue assays. Similarly, to FOH and GGOH, it was observed that phytol (POH), a 20-carbon plant isoprenoid, as well as unsaponifiable lipid extracts from foods rescue parasites from the antimalarial effect of fosmidomycin. Contrarily, neither dolichols nor nonaprenol rescue parasites from fosmidomycin. Considering this, here we characterized the transport of FOH, GGOH, and POH. Once incorporated, it was observed that these substances are phosphorylated, condensed into longer isoprenoid alcohols, and incorporated into proteins and dolichyl phosphates. Through proteomic and radiolabelling approaches, it was found that prenylated proteins are naturally attached to several isoprenoids, derived from GGOH, dolichol, and POH if exogenously added. Furthermore, the results suggest the presence of at least two promiscuous protein prenyltransferases in the parasite: one enzyme which can use FPP among other unidentified substrates and another enzyme that can use GGPP, phytyl pyrophosphate (PPP), and dolichols, among other substrates not identified here. Thus, further evidence was obtained for dolichols and other isoprenoid products attached to proteins. This study helps to better understand the apicoplast-targeting antimalarial mechanism of action and a novel post-translational modification of proteins in P. falciparum.