Structural activity relationship of metallo-aminoquines as a next generation antimalarials

Apicomplexian parasite of the genus Plasmodium is the causative agent of malaria, one of the most devastating, furious and common infectious disease throughout the world. According to the latest World malaria report, there were 229 million cases of malaria in 2019 majorly consisting of children under 5 years of age. Some of known analogues viz. quinine, quinoline-containing compounds have been used for last century in the clinical treatment of malaria. Past few decades have witnessed the emergence of multi-drug resistance (MDR) strains of Plasmodium species to existing antimalarials pressing the need for new drug candidates. For the past few decades bioorganometallic approach to malaria therapy has been introduced which led to the discovery of noval metalcontaining aminoquinolines analogues viz. ferroquine (FQ or 1), Ruthenoquine (RQ or 2) and other related potent metal-analogues. It observed that some metal containing analogues (Fe-, Rh-, Ru-, Re-, Au-, Zn-, Cr-, Pd-, Sn-, Cd-, Ir-, Co-, Cu-, and Mn-aminoquines) were more potent; however, some were equally potent as Chloroquine (CQ) and 1. This is probably due to the intertion of metals in the CQ via various approaches, which might be a very attractive strategy to develop a SAR of novel metal containing antimalarials. Thus, this review aims to summarize the SAR of metal containing aminoquines towards the discovery of potent antimalarial hybrids to provide an insight for rational designs of more effective and less toxic metal containing amoniquines.

The Potential use of a Curcumin-Piperine Combination as an Antimalarial Agent: A Systematic Review

Malaria remains a significant global health problem, but the development of effective antimalarial drugs is challenging due to the parasite’s complex life cycle and lack of knowledge about the critical specific stages. Medicinal plants have been investigated as adjuvant therapy for malaria, so this systematic review summarizes 46 primary articles published until December 2020 that discuss curcumin and piperine as antimalarial agents. The selected articles discussed their antioxidant, anti-inflammatory, and antiapoptosis properties, as well as their mechanism of action against Plasmodium species. Curcumin is a potent antioxidant, damages parasite DNA, and may promote an immune response against Plasmodium by increasing reactive oxygen species (ROS), while piperine is also a potent antioxidant that potentiates the effects of curcumin. Hence, combining these compounds is likely to have the same effect as chloroquine, that is, attenuate and restrict parasite development, thereby reducing parasitemia and increasing host survival. This systematic review presents new information regarding the development of a curcumin-piperine combination for future malaria therapy.

Ethanol Extract of Areca Nuts was Able to Improve the Histopathological Features of P. Berghei-Induced Liver Damage in Mice

Adequate therapy is necessary to prevent further damage to the liver infected with Plasmodium sp. Areca catechu and curcumin have the potential for malaria therapy, and scientific evidence is required to examine such potential either alone or in combination. This experimental study used a posttest-only group design involving 24 male Swiss mice (Mus musculus) as the subjects divided into 6 groups (@4 mice). P. berghei was injected intraperitoneally in 5 groups, and different types of treatment (4 days, feeding tube) were administered to 4 groups (K1 = chloroquine, K3 = ethanol extract of Areca nuts + curcumin, K4 = ethanol extract of Areca nuts, K5 = curcumin). The doses were 0.012mg/kgBW of chloroquine, 150mg/kgBW of Areca nut ethanol extract, and 30mg/kgBW of curcumin. K2 was the unhealthy group (infected with P. berghei without therapy), while K6 was the normal/healthy group. Parasitemia was examined in 3 days after induction by P. berghei (inclusion criterion: parasitemia >5%, exclusion criterion: parasitemia >15%). The liver was embedded in paraffin blocks and stained with HE. Observations were made to identify the presence of necrosis, portal inflammation, and hemosiderin. The data of histopathological changes in the liver was expressed in percentages. The administration of Areca nut ethanol extract was able to provide better histopathological features than curcumin therapy alone, in combination, or chloroquine therapy (K4, no necrosis; mild portal inflammation = 50%, moderate = 25%; hemosiderin = 25%). Areca nut ethanol extract had yet to show histopathological features that resembled a healthy condition (K6 = normal inflammation, mild, moderate = 50%, 50%, 0%, respectively; hemosiderin = 0%). The ethanol extract of Areca nuts alone was shortly able to improve the histopathological features of P. berghei-induced liver damage in mice. Keywords: Areca nuts, Plasmodium berghei, histopathology of liver

Molecular Approaches for Malaria Therapy

Malaria is a potentially fatal blood disease spread by mosquitos. Malaria is preventable, but it is more prevalent in developing countries where prevention is difficult and prophylaxis is often inaccessible. Malaria remains one of the world’s most serious public health problems, according to the World Health Organisation (WHO). The development of resistance is a current problem that poses a danger to the environment. Resistance is a current problem that could jeopardise the use of well-established and cost-effective antimalarials. The World Health Organisation recommends an artemisinin-based drug combination (ACT) to avoid or postpone the development of resistance. This book’s chapter discusses current medicines as well as potential and rational possibilities for finding new drugs to treat malady. There were also WHO recommendations for both complicated and non-complicated malaria. Other preventive measures such as ITN and IPT are listed in the manuscript in addition to routine care. While a brief overview of the vaccine tested so far has been included, there is currently no vaccine available to treat malaria.

Targeting SUMOylation in Plasmodium as a Potential Target for Malaria Therapy

Malaria is a parasitic disease that represents a public health problem worldwide. Protozoans of the Plasmodium genus are responsible for causing malaria in humans. Plasmodium species have a complex life cycle that requires post-translational modifications (PTMs) to control cellular activities temporally and spatially and regulate the levels of critical proteins and cellular mechanisms for maintaining an efficient infection and immune evasion. SUMOylation is a PTM formed by the covalent linkage of a small ubiquitin-like modifier protein to the lysine residues on the protein substrate. This PTM is reversible and is triggered by the sequential action of three enzymes: E1-activating, E2-conjugating, and E3 ligase. On the other end, ubiquitin-like-protein-specific proteases in yeast and sentrin-specific proteases in mammals are responsible for processing SUMO peptides and for deconjugating SUMOylated moieties. Further studies are necessary to comprehend the molecular mechanisms and cellular functions of SUMO in Plasmodium. The emergence of drug-resistant malaria parasites prompts the discovery of new targets and antimalarial drugs with novel mechanisms of action. In this scenario, the conserved biological processes regulated by SUMOylation in the malaria parasites such as gene expression regulation, oxidative stress response, ubiquitylation, and proteasome pathways, suggest PfSUMO as a new potential drug target. This mini-review focuses on the current understanding of the mechanism of action of the PfSUMO during the coordinated multi-step life cycle of Plasmodium and discusses them as attractive new target proteins for the development of parasite-specific inhibitors and therapeutic intervention toward malaria disease.

Isolation and structure elucidation of anti-malarial principles from Terminalia mantaly H. Perrier stem bark

Emergence of malaria parasite resistance to drugs has raised global public health concerns for a compelling need to develop improved malaria therapy. This study is a bio-guided isolation of triterpenoid antimalarial compounds from Terminalia mantaly. Methanol extract of the plant was subjected to column chromatography, and eluted with a ternary solvent system gradient-wise. Two compounds, 1 and 2, were isolated and characterised by spectroscopic data (IR, 1H and 13C NMR, COSY, HMQC, HMBC) and by comparison with literature. Isolated compounds were investigated for antimalarial property by spectrophotometric determination of inhibition of β-Hematin formation, absorbance taken at 405 nm. Results were analysed using Graghpad Prism® (6.0) and presented as mean IC50±SEM. Statistical significance, determined using Student’s t-test and one-way ANOVA, set at p-value of 0.05. Quantitative β-Hematin formation inhibitory activities gave IC50±SEM values of (compound 1; 4.434±0.47), (compound 2; 5.140±4.2) with (chloroquine; 0.335±0.1 mg/ml). Compound 1 was identified as 2,3,19,23-tetrahydroxyolean-12-en-28-oic acid glucopyranoside (arjunglucoside I), and compound2 as its aglycone, 2,3,19,23-tetrahydroxyolean-12-en-28-oic acid (arjungenin). This study provided credence for folkloric use of Terminalia mantaly to treat malaria, and this observed activity was probably due to these isolated triterpenoids.Keywords: β-Hematin, triterpenoids, nuclear magnetic resonance spectroscopy

Antiplasmodial Compounds from Deep-Water Marine Invertebrates

Novel drug leads for malaria therapy are urgently needed because of the widespread emergence of resistance to all available drugs. Screening of the Harbor Branch enriched fraction library against the Plasmodium falciparum chloroquine-resistant strain (Dd2) followed by bioassay-guided fractionation led to the identification of two potent antiplasmodials; a novel diterpene designated as bebrycin A (1) and the known C21 degraded terpene nitenin (2). A SYBR Green I assay was used to establish a Dd2 EC50 of 1.08 ± 0.21 and 0.29 ± 0.02 µM for bebrycin A and nitenin, respectively. Further analysis was then performed to assess the stage specificity of the inhibitors antiplasmodial effects on the Dd2 intraerythrocytic life cycle. Exposure to bebrycin A was found to block parasite maturation at the schizont stage if added any time prior to late schizogony at 42 hours post invasion, (HPI). In contrast, early life cycle exposure to nitenin (prior to 18 HPI) was identified as crucial to parasite inhibition, suggesting nitenin may target the maturation of the parasite during the transition from ring to early trophozoite (6–18 HPI), a novel property among known antimalarials.

Identification and Assessment of Plasmodium berghei Merozoites and Cell Cycle by Flow Cytometry

ABSTRACT Background The asexual blood stages of the Plasmodium berghei life cycle including merozoites are attractive targets for transmission blocking vaccines and drugs. Improved understanding of P. berghei life cycle stage growth and development would provide new opportunities to evaluate antimalarial vaccines and drugs. Methods Blood stage samples from C57BL/6 albino mice infected with P. berghei sporozoites were singly stained with a high binding affinity deoxyribonucleic acid dye, YOYO-1, and measured by flow cytometry (FCM). Duplicate slides were made from samples and stained with diluted Giemsa’s and YOYO-1, respectively. Correlated results were compared by FCM, light microscopy, and fluorescent microscopy. Results Complete life cycle stage determination and analysis by FCM is reported to include merozoites, ring forms, trophozoites, immature, and mature schizonts. FCM demonstrated a clear separation between each stage using their unique fluorescence distribution. When compared to light microscopy, a strong correlation (r 2 = 0.925 to 0.974) was observed in determining the ring forms, trophozoites, and schizonts phases, but only a moderate correlation (r 2 = 0.684 to 0.778) was observed for merozoites. The identification and measurement of merozoites suggest that FCM is a useful technique to monitor the entire life stage of the parasite. Initial stage-specific data demonstrated that mefloquine has a mode of action on mature parasite forms, and artesunic acid was rapidly effective against merozoites and other immature and mature parasite forms with higher killing. Conclusion Blood stage parasites in each individual life stage, including merozoites, are reliably identified and quantified quickly by FCM, making this technique an ideal alternative to microscopy. This integrated whole life stage model, particularly with confirmed determination of merozoite population, could widely be used for drug and vaccine research in malaria therapy and prophylaxis.