1,2,4,5-Tetraoxane derivatives/hybrids as potent antimalarial endoperoxides: Chronological advancements, structure-activity relationship (SAR) studies and future perspectives.

Malaria is a life-threatening disease that affects tropical and subtropical regions worldwide. Various drugs were used to treat malaria, including artemisinin and derivatives, antibiotics (tetracycline, doxycycline), quinolines (chloroquine, amodiaquine), and folate antagonists (sulfadoxine and pyrimethamine). Since the malarial parasites developed drug resistance, there is a need to develop new chemical entities with high efficacy and low toxicity. In this context, 1,2,4,5-tetraoxanes emerged as an essential scaffold and have shown promising antimalarial activity. To improve activity and overcome resistance to various antimalarial drugs; 1,2,4,5-tetraoxanes were fused with various aryl/heteroaryl/alicyclic/spiro moieties (steroid-based 1,2,4,5-tetraoxanes, triazine-based 1,2,4,5-tetraoxanes, aminoquinoline-based 1,2,4,5-tetraoxanes, dispiro-based 1,2,4,5-tetraoxanes, piperidine-based 1,2,4,5-tetraoxanes and diaryl-based 1,2,4,5-tetraoxanes). The present review aims to focus on covering the relevant literature published during the past 30 years (1992-2022). We summarize the most significant in vitro, in vivo results and structure-activity relationship studies of 1,2,4,5-tetraoxane-based hybrids as antimalarial agents. The structural evolution of different hybrids can provide the framework for the future development of 1,2,4,5-tetraoxane-based hybrids to treat malaria.

Preliminary insight on diarylpentanoids as potential antimalarials: In silico, in vitro pLDH and in vivo zebrafish toxicity assessment.

Malaria remains a major public health problem worldwide, including in Southeast Asia. Chemotherapeutic agents such as chloroquine (CQ) are effective, but problems with drug resistance and toxicity have necessitated a continuous search for new effective antimalarial agents. Here we report on a virtual screening of ∼300 diarylpentanoids and derivatives, in search of potential Plasmodium falciparum lactate dehydrogenase (PfLDH) inhibitors with acceptable drug-like properties. Several molecules with binding affinities comparable to CQ were chosen for in vitro validation of antimalarial efficacy. Among them, MS33A, MS33C and MS34C are the most promising against CQ-sensitive (3D7) with EC50 values of 1.6, 2.5 and 3.1 µM, respectively. Meanwhile, MS87 (EC50 of 1.85 µM) shown the most active against the CQ-resistant Gombak A strain, and MS33A and MS33C the most effective P. knowlesi inhibitors (EC50 of 3.6 and 5.1 µM, respectively). The in vitro cytotoxicity of selected diarylpentanoids (MS33A, MS33C, MS34C and MS87) was tested on Vero mammalian cells to evaluate parasite selectivity (SI), showing moderate to low cytotoxicity (CC50 > 82 µM). In addition, MS87 exhibited a high SI and the lowest resistance index (RI), suggesting that MS87 may exert effective parasite inhibition with low resistance potential in the CQ-resistant P. falciparum strain. Furthermore, the in vivo toxicity of the molecules on early embryonic development, the cardiovascular system, heart rate, motor activity and apoptosis were assessed in a zebrafish animal model. The overall results indicate the preliminary potential of diarylpentanoids, which need further investigation for their development as new antimalarial agents.

Novel ether derivatives of 11-azaartemisinins with high order antimalarial activity against multidrug-resistant Plasmodium yoelii in Swiss mice.

This study investigates cutting-edge synthetic chemistry approaches for designing and producing innovative antimalarial drugs with improved efficacy and fewer adverse effects. Novel amino (-NH2) and hydroxy (-OH) functionalized 11-azaartemisinins 9, 12, and 14 were synthesized along with their derivatives 11a, 13a-e, and 15a-b through ART and were tested for their AMA (antimalarial activity) against Plasmodium yoelii via intramuscular (i.m.) and oral routes in Swiss mice. Ether derivative 13c was the most active compound by i.m. route, it has shown 100 % protection at the dose of 12 mg/kg × 4 days and showed 100 % clearance of parasitaemia on day 4 at dose of 6 mg/kg. Amine 11a, ether derivatives 13d, 13e and ether 15a also showed promising antimalarial activity. ß-Arteether gave 100 % protection at the dose of 48 mg/kg × 4 days and 20 % protection at 24 mg/kg × 4 days dose by oral route, while it showed 100 % protection at 6 mg/kg × 4 days and no protection at 3 mg/kg × 4 days by i.m. route.

In vivo antimalarial effect of 1-hydroxy-5,6,7-trimethoxyxanthone isolated from Mammea siamensis T. Anders. flowers: pharmacokinetic and acute toxicity studies.

BACKGROUND: The potent antiplasmodial activity of 1-hydroxy-5,6,7-trimethoxyxanthone (HTX), isolated from Mammea siamensis T. Anders. flowers, has previously been demonstrated in vitro. However, its in vivo activity has not been reported. Therefore, this study aimed to investigate the antimalarial activity and acute toxicity of HTX in a mouse model and to evaluate the pharmacokinetic profile of HTX following a single intraperitoneal administration. METHODS: The in vivo antimalarial activity of HTX was evaluated using a 4-day suppressive test. Mice were intraperitoneally injected with Plasmodium berghei ANKA strain and given HTX daily for 4 days. To detect acute toxicity, mice received a single dose of HTX and were observed for 14 days. Additionally, the biochemical parameters of the liver and kidney functions as well as the histopathology of liver and kidney tissues were examined. HTX pharmacokinetics after intraperitoneal administration was also investigated in a mouse model. Liquid chromatography triple quadrupole mass spectrometry was used to quantify plasma HTX and calculate pharmacokinetic parameters with the PKSolver software. RESULTS: HTX at 10 mg/kg body weight significantly suppressed parasitemia in malaria-infected mice by 74.26%. Mice treated with 3 mg/kg HTX showed 46.88% suppression, whereas mice treated with 1 mg/kg displayed 34.56% suppression. Additionally, no symptoms of acute toxicity were observed in the HTX-treated groups. There were no significant alterations in the biochemical parameters of the liver and kidney functions and no histological changes in liver or kidney tissues. Following intraperitoneal HTX administration, the pharmacokinetic profile exhibited a maximum concentration (Cmax) of 94.02 ng/mL, time to attain Cmax (Tmax) of 0.5 h, mean resident time of 14.80 h, and elimination half-life of 13.88 h. CONCLUSIONS: HTX has in vivo antimalarial properties against P. berghei infection. Acute toxicity studies of HTX did not show behavioral changes or mortality. The median lethal dose was greater than 50 mg/kg body weight. Pharmacokinetic studies showed that HTX has a long elimination half-life; hence, shortening the duration of malaria treatment may be required to minimize toxicity.

Synthesis of Novel Artemisinin, Ciprofloxacin, and Norfloxacin Hybrids with Potent Antiplasmodial Activity.

The synthesis and antiplasmodial evaluation of new hybrids combining the pharmacophore structures of artemisinin, ciprofloxacin or norfloxacin, and 7-chloroquinoline are reported in this study. The first step for all of the syntheses is the obtainment of key piperazine esters intermediates bearing the drugs ciprofloxacin and norfloxacin. Using these platforms, 18 final compounds were synthesized through a multistep procedure with overall yields ranging between 8 and 20%. All compounds were screened for their antiplasmodial activity against the chloroquine-resistant Plasmodium falciparum FcB1 strain. Compounds 20, 21, 22, and 28, bearing an artesunate fragment with ciprofloxacin, exhibited IC50 values in the range of 3.5-5.4 nM and excellent selectivity indices. Among the compounds bearing the artesunate moiety on the norfloxacin, two of them, 23 and 24, afforded IC50 values of 1.5 nM and 1.9 nM, respectively. They also showed excellent selectivity indices. The most potent compounds were also evaluated against the CQ-resistant Dd2 strain of Plasmodium falciparum, demonstrating that those compounds incorporating the artesunate fragment were the most potent. Finally, the combination of artesunate with either ciprofloxacin or norfloxacin moieties in a single molecular entity proved to substantially enhance the activity and selectivity when compared to the administration of the unconjugated counterparts artesunate/ciprofloxacin and artesunate/norfloxacin.

Effects of seasonal variation on phytochemicals contributing to the antimalarial and antitrypanosomal activities of Breonadia salicina using a metabolomic approach.

This study involves the investigation of various plant parts of Breonadia salicina (Vahl) Hepper and J.R.I. Wood across multiple consecutive seasons. It aims to delve into the phytochemistry of these different plant parts and establish connections between the findings and their biological activities. This comprehensive approach employs metabolomics techniques, with the ultimate goal of exploring the potential for drug development. Samples were collected in Fondwe, a village in Limpopo (South Africa), based on local reports of the efficacy of this plant used by traditional healers in the area. The antimalarial and antitrypanosomal activities of samples collected over the seasons were determined with the parasite lactate dehydrogenase (pLDH) and specific Trypanosoma brucei assays, respectively. Consequently, a total of 24 compounds were tentatively identified through ultra-performance liquid chromatography with quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS). Chemical profiles of the different plant parts of Breonadia salicina collected in different seasons produced contrasting metabolic profiles. Chemometric analysis of the UPLC-QTOF-MS data enabled us to determine the chemical variability of the crude stem bark, root and leaf extracts (n = 48) collected over four consecutive seasons by evaluating the metabolomics fingerprinting of the samples using an untargeted approach. Principal component analysis (PCA), hierarchical cluster analysis (HCA), and partial least squares discriminant analysis (PLS-DA) indicated the existence of two key clusters that are linked to the root, stem bark, and leaves. The stem and root chemistry differed from that of the leaves. Seasonal variations were noted in each plant part, with autumn and winter samples closely grouped compared to spring and summer samples in the methanol leaf extracts. Biochemometric analysis could not relate specific compounds to the antimalarial and antitrypanosomal activities of the active extracts, underscoring the intricate interactions among the secondary metabolites. This study further confirms the optimal plant parts to collect in each season for the most effective antimalarial and antitrypanosomal activities.

A Review on Synthetic Thiazole Derivatives as an Antimalarial Agent.

BACKGROUND: Thiazole is a widely studied core structure in heterocyclic chemistry and has proven to be a valuable scaffold in medicinal chemistry. The presence of thiazole in both naturally occurring and synthetic pharmacologically active compounds demonstrates the adaptability of these derivatives. METHODS: The current study attempted to review and compile the contributions of numerous researchers over the last 20 years to the medicinal importance of these scaffolds, with a primary focus on antimalarial activity. The review is based on an extensive search of PubMed, Google Scholar, Elsevier, and other renowned journal sites for a thorough literature survey involving various research and review articles. RESULTS: A comprehensive review of the antimalarial activity of the thiazole scaffold revealed potential therapeutic targets in Plasmodium species. Furthermore, the correlation of structure-activity-relationship (SAR) studies from various articles suggests that the thiazole ring has therapeutic potential. CONCLUSION: This article intends to point researchers in the right direction for developing potential thiazole-based compounds as antimalarial agents in the future.

Exploring the antimalarial and antioxidant efficacy of transition metal(II) chelates of thiosemicarbazone ligands: spectral investigations, molecular docking, DFT, MESP and ADMET.

Malaria, a relentless and ancient adversary, continues to cast its shadow over vast swathes of the globe, afflicting millions of people and have a heavy toll on human health and well-being. Despite substantial progress in the fight against this parasitic disease in recent decades, malaria still persists as a substantial global health concern, especially in some specific region which have limited resources and vulnerable populations. Thus, to ascertain an combating agent for malaria and its associated dysfunction, 4-(4-ethylphenyl)-3-thiosemicarbazide and benzaldehydes based two new thiosemicarbazone ligands (1-2) and their cobalt(II), nickel(II), copper(II), zinc(II) metal complexes (3-10) were synthesized in the present research work. The synthesized compounds were comprehensive characterized through spectral and physical investigations, demonstrating octahedral stereochemistry of the complexes. Further, the antimalarial and antioxidant potential of the compounds (1-10) were analyzed by micro assay and DPPH assay protocols, respectively, to examine the therapeutic aspect of the compounds. The performed biological evaluations revealed that the complexes are more efficient in controlling infectious ailment in comparison of ligands. The complexes (5), (6), (10) shows significant efficiency for malarial and oxidant dysfunctions whereas Zn(II) complex (6) exhibit highest potency with 1.02 ± 0.07 and 2.28 ± 0.05 µM IC50 value. Furthermore, to support the highest antimalarial potency of the (3-6) complexes and their associated ligand (1), the computational studies like molecular docking, DFT, MESP and ADMET analysis were executed which were supported the biological efficacy of the complex (6) by providing numerous parameters like binding interaction electronegativity, electrophilicity, HOMO value and electron density.

Ceramicines U-Z from Chisocheton ceramicus and structure-antimalarial activity relationship study.

Ceramicines are a series of limonoids which were isolated from the barks of Malaysian Chisocheton ceramicus (Meliaceae), and were known to show various biological activity. Six new limonoids, ceramicines U-Z (1-6), with a cyclopentanone[α]phenanthrene ring system with a ß-furyl ring at C-17 were isolated from the barks of C. ceramicus. Their structures were determined on the basis of the 1D and 2D NMR analyses, and their absolute configurations were investigated by CD spectroscopy. Ceramicine W (3) exhibited potent antimalarial activity against Plasmodium falciparum 3D7 strain with IC50 value of 1.2 µM. In addition, the structure-antimalarial activity relationship (SAR) of the ceramicines was investigated to identify substituent patterns that may enhance activity. It appears that ring B and the functional groups in the vicinity of rings B and C are critical for the antimalarial activity of the ceramicines. In particular, bulky ester substituents with equatorial orientation at C-7 and C-12 greatly increase the antimalarial activity.

Recent advances in the synthesis and antimalarial activity of 1,2,4-trioxanes.

The increasing resistance of various malarial parasite strains to drugs has made the production of a new, rapid-acting, and efficient antimalarial drug more necessary, as the demand for such drugs is growing rapidly. As a major global health concern, various methods have been implemented to address the problem of drug resistance, including the hybrid drug concept, combination therapy, the development of analogues of existing medicines, and the use of drug resistance reversal agents. Artemisinin and its derivatives are currently used against multidrug- resistant P. falciparum species. However, due to its natural origin, its use has been limited by its scarcity in natural resources. As a result, finding a substitute becomes more crucial, and the peroxide group in artemisinin, responsible for the drugs biological action in the form of 1,2,4-trioxane, may hold the key to resolving this issue. The literature suggests that 1,2,4-trioxanes have the potential to become an alternative to current malaria drugs, as highlighted in this review. This is why 1,2,4-trioxanes and their derivatives have been synthesized on a large scale worldwide, as they have shown promising antimalarial activity in vivo and in vitro against Plasmodium species. Consequently, the search for a more convenient, environment friendly, sustainable, efficient, and effective synthetic pathway for the synthesis of 1,2,4-trioxanes continues. The aim of this work is to provide a comprehensive analysis of the synthesis and mechanism of action of 1,2,4-trioxanes. This systematic review highlights the most recent summaries of derivatives of 1,2,4-trioxane compounds and dimers with potential antimalarial activity from January 1988 to 2023.

Novel amino- and hydroxy-functionalized 1,2,4-trioxanes and their antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice via intramuscular and oral route.

Following the economic and social state of humanity, Malaria is categorized as one of the life-threatening illness epidemics in under developed countries. For the eradication of the same, 1,2,4-trioxanes 17a1-a2, 17b1-b2, 17c1-c2 15a-c, 18 and 19 have been synthesized continuing the creation of a novel series. Additionally, these novel compounds were tested for their effectiveness against the multidrug-resistant Plasmodium yoelii nigeriensis in mice model using both oral and intramuscular (im) administration routes. The two most potent compounds of the series, 17a1 and 17a2, demonstrated 100 % protection at 48 mg/kg x 4 days via oral route, which is twice as potent as artemisinin. In this model artemisinin provided 100 % protection at a dose of 48 mg/kg × 4 days and 80 % protection at 24 mg/kg × 4 days via im route.

An overview on the antimalarial activity of 1,2,4-trioxanes, 1,2,4-trioxolanes and 1,2,4,5-tetraoxanes.

The demand for novel, fast-acting, and effective antimalarial medications is increasing exponentially. Multidrug resistant forms of malarial parasites, which are rapidly spreading, pose a serious threat to global health. Drug resistance has been addressed using a variety of strategies, such as targeted therapies, the hybrid drug idea, the development of advanced analogues of pre-existing drugs, and the hybrid model of resistant strains control mechanisms. Additionally, the demand for discovering new potent drugs grows due to the prolonged life cycle of conventional therapy brought on by the emergence of resistant strains and ongoing changes in existing therapies. The 1,2,4-trioxane ring system in artemisinin (ART) is the most significant endoperoxide structural scaffold and is thought to be the key pharmacophoric moiety required for the pharmacodynamic potential of endoperoxide-based antimalarials. Several derivatives of artemisinin have also been found as potential treatments for multidrug-resistant strain in this area. Many 1,2,4-trioxanes, 1,2,4-trioxolanes, and 1,2,4,5-tetraoxanes derivatives have been synthesised as a result, and many of these have shown promise antimalarial activity both in vivo and in vitro against Plasmodium parasites. As a consequence, efforts to develop a functionally straight-forward, less expensive, and vastly more effective synthetic pathway to trioxanes continue. This study aims to give a thorough examination of the biological properties and mode of action of endoperoxide compounds derived from 1,2,4-trioxane-based functional scaffolds. The present system of 1,2,4-trioxane, 1,2,4-trioxolane, and 1,2,4,5-tetraoxane compounds and dimers with potentially antimalarial activity will be highlighted in this systematic review (January 1963-December 2022).

An Overview on Antimalarial Peptides: Natural Sources, Synthetic Methodology and Biological Properties.

Peptide compounds play a significant role in medicinal chemistry as they can inhibit the activity of species that cause malaria. This literature review summarizes the isolation of antimalarial peptides, the synthesis method with the detailed structure and sequences of each peptide, and discusses the biological activity of the isolated and synthesized compounds. The synthetic routes and reactions for cyclic and linear antimalarial peptides are systematically highlighted in this review including preparing building blocks, protection and deprotection, coupling and cyclization reactions until the target compound is obtained. Based on the literature data and the results, this review's aim is to provide information to discover and synthesize more antimalarial peptide for future research.

Antimalarial activities of benzothiazole analogs: A systematic review.

BACKGROUND: Benzothiazole derivatives have been reported to possess a wide range of biological activities, including antimalarial activity. This systematic review aims to summarize and evaluate the antimalarial activities of benzothiazole analogs. METHODS: We conducted an electronic search using nine databases in October 2017 and subsequently updated in September 2022. We included all original in vitro and in vivo studies that documented the antimalarial activities of compounds containing benzothiazole analogs with no restriction. The risk of bias of each included study was assessed by ToxRTool. RESULTS: Twenty-eight articles were included in our study, which are in vitro, in vivo, or both. Of these, 232 substances were identified to have potent antiplasmodial activity against various strains of the malaria parasite. Benzothiazole analogs show different antimalarial mechanisms, including inhibition of Plasmodium falciparum enzymes in in vitro studies and inhibition of blood parasites in in vivo studies. CONCLUSIONS: Benzothiazole derivatives are promising substances for treating malaria. The structure-activity relationship studies suggest that the substitution pattern of the benzothiazole scaffold plays a crucial role in determining the antimalarial activity of the analog.

Antimalarial Activity of Anacardium occidentale Leaf Extracts Against Plasmodium falciparum Transketolase (PfTK).

BACKGROUND: As per estimates by WHO in 2021 almost half of the world's population was at risk of malaria and > 0.6 million deaths were attributed to malaria. Therefore, the present study was aimed to explore the antimalarial activity of extracts derived from the leaves of the plant Anacardium occidentale L., which has been used traditionally for the treatment of malaria. Different extracts of A. occidentale leaves were prepared and tested for their inhibitory activity against recombinant P. falciparum transketolase (rPfTK) enzyme, in vitro. Further, growth inhibitory activity against cultivated blood stage P. falciparum parasites (3D7 strain), was studied using SYBR Green fluorescence-based in vitro assays. Acute toxicity of the hydro alcoholic extracts of leaves of A. occidentale (HELA) at different concentrations was evaluated on mice and Zebra fish embryos. HELA showed 75.45 ± 0.35% inhibitory activity against the recombinant PfTk and 99.31 ± 0.08% growth inhibition against intra-erythrocytic stages of P. falciparum at the maximum concentration (50 µg/ml) with IC50 of 4.17 ± 0.22 µg/ml. The toxicity test results showed that the heartbeat, somite formation, tail detachment and hatching of embryos were not affected when Zebra fish embryos were treated with 0.1 to 10 µg/ml of the extract. However, at higher concentrations of the extract, at 48 h (1000 µg/ml) and 96 h (100 µg/ml and 1000 µg/ml, respectively) there was no heartbeat in the fish embryos. In the acute oral toxicity tests performed on mice, the extract showed no toxicity up to 300 mg/kg body weight in mice. CONCLUSION: The hydro-alcoholic extract of leaves of A. occidentale L. showed potent antimalarial activity against blood stage P. falciparum. Based on the observed inhibitory activity on the transketolase enzyme of P. falciparum it is likely that this enzyme is the target for the development of bioactive molecules present in the plant extracts. The promising anti-malarial activity of purified compounds from leaves of A. occidentale needs to be further explored for development of new anti-malarial therapy.

Antimalarial and neuroprotective ent-abietane diterpenoids from the aerial parts of Phlogacanthus curviflorus.

Six new ent-abietane diterpenoids, abientaphlogatones A-F (1-6), along with two undescribed ent-abietane diterpenoid glucosides, abientaphlogasides A-B (7-8) and four known analogs were isolated from the aerial parts ofPhlogacanthus curviflorus (P. curviflorus). The structures of these compounds were determined using high-resolution electrospray ionization mass spectrometry (HR-ESI-MS), one-dimensional and two-dimensional nuclear magnetic resonance (NMR) spectroscopy, electronic circular dichroism (ECD) spectra, and quantum chemical calculations. Notably, compounds 5 and 6 represented the first reported instances of ent-norabietane diterpenoids from the genus Phlogacanthus. In the ß-hematin formation inhibition assay, compounds 2, 4, 7-10, and 12 displayed antimalarial activity, with IC50 values of 12.97-65.01 µmol·L-1. Furthermore, compounds 4, 5, 8, and 10 demonstrated neuroprotective activity in PC12 cell injury models induced by H2O2 and MPP+.

Synthesis, Characterization, Antimicrobial and Antimalarial Activities of Azines Based Schiff Bases and their Pd(II) Complexes.

Herein, we report synthesis, characterization, antimicrobial and antimalarial activities of azines Schiff base ligands (L1 -L4 ) and their palladium (II) complexes (C1 -C4 ) of [Pd(L)(OAc)2 ] type. The azine ligands (L1 -L4 ) were prepared by condensation of carbonyl compounds with hydrazine hydrate and their complexes by the reaction of palladium acetate with L1 -L4 ligands in 1 : 1 molar ratio. The prepared ligands and their complexes were characterized by spectral characterization using 1 H &13 C-NMR, FT-IR and mass spectral studies, which revealed that the ligands coordinates via azomethine nitrogen and heteroatom or aryl carbon with palladium. Moreover, Schiff bases and their palladium (II) complexes have been screened for their antibacterial (S. aureus, B. subtillis, and S. typhi, P. aeruginosa), antifungal (C. albicans, A. niger, and A. clavatus) and antimalarial (P. falciparum) activities. The Schiff base L4 showed good results for antibacterial against S. aureus (MIC, 50 µg/mL) and antimalarial against P. falciparum (IC50 , 0.83 µg/mL). The complex C1 showed best antibacterial activity (MIC, 62.5 µg/mL) against S. typhi and the complex C4 exhibited remarkable antimalarial activity (IC50 , 0.42 µg/mL) among the tested compounds. Thus, azines based ligands and their Pd complexes can be good antimicrobial and antimalarial agents if explored further.

Current advances in nanodrug delivery systems for malaria prevention and treatment.

Malaria is a life-threatening, blood-borne disease with over two hundred million cases throughout the world and is more prevalent in Sub-Saharan Africa than anywhere else in the world. Over the years, several treatment agents have been developed for malaria; however, most of these active pharmaceutical ingredients exhibit poor aqueous solubility and low bioavailability and may result in drug-resistant parasites, thus increasing malaria cases and eventually, deaths. Factors such as these in therapeutics have led to a better appreciation of nanomaterials. The ability of nanomaterials to function as drug carriers with a high loading capacity and targeted drug delivery, good biocompatibility, and low toxicity renders them an appealing alternative to conventional therapy. Nanomaterials such as dendrimers and liposomes have been demonstrated to be capable of enhancing the efficacy of antimalarial drugs. This review discusses the recent development of nanomaterials and their benefits in drug delivery for the potential treatment of malaria.

Preclinical evaluation of antimalarial activity of CPF-1 formulation as an alternative choice for the treatment of malaria.

BACKGROUND: Kheaw Hom remedy is a traditional Thai medicine used to treat fever. Some plants used in the Kheaw Hom remedy show promising in vitro antimalarial activity. This study prepared novel formulations of plants from the Kheaw Hom remedy and evaluated their antimalarial and toxicological activities. METHODS: Seven new formulations were prepared by combining at least three herbs of six selected plants from the Kheaw Hom remedy, namely Mammea siamensis Kosterm., Mesua ferrea L., Dracaena loureiroi Gagnep., Pogostemon cablin (Blanco) Benth., Kaempferia galanga L, and Eupatorium stoechadosmum Hance. In vitro antimalarial activities of each formulation's aqueous and ethanolic extracts were evaluated using the parasite lactate dehydrogenase (pLDH) assay. Cytotoxicity in Vero and HepG2 cells was assessed using the MTT assay. An extract with good antimalarial potency and selectivity index (SI) was selected for in vivo antimalarial activity using Peter's 4-day suppressive test and acute oral toxicity test in mice. In addition, bioactive compounds were identified using Gas chromatography-mass spectrometry (GC-MS) analysis. RESULTS: Among the seven new formulations, ethanolic extracts of CPF-1 (Formulation 1) showed the highest activity with an IC50 value of 1.32 ± 0.66 µg/ml, followed by ethanolic extracts of Formulation 4 and Formulation 6 with an IC50 value of 1.52 ± 0.28 µg/ml and 2.48 ± 0.34 µg/ml, respectively. The highest SI values were obtained for the ethanolic extract of CPF-1 that was selected to confirm its in vivo antimalarial activity and toxicity. The results demonstrated a significant dose-dependent reduction in parasitemia. Maximum suppressive effect of the extract (72.01%) was observed at the highest dose administered (600 mg/kg). No significant toxicity was observed after the administration of 2000 mg/kg. Using GC-MS analysis, the most abundant compound in the ethanolic extract of CPF-1 was ethyl p-methoxycinnamate (14.32%), followed by 2-propenoic acid, 3-phenyl-, ethyl ester, (E)- (2.50%), and pentadecane (1.85%). CONCLUSION: The ethanolic extract of CPF-1 showed promising in vitro and in vivo antimalarial efficacy, with no toxic effects at a dose of 2000 mg/kg, suggesting that the ethanolic extract of CPF-1 may serves as a new herbal formulation for the treatment of malaria. Additional research is required for safety and clinical pharmacology studies.

Antimalarial ceramicines Q-T from Chisocheton ceramicus.

Ceramicines are a series of limonoids that were isolated from the bark of Malaysian Chisocheton ceramicus (Meliaceae) and were known to show various biological activity. Four new limonoids, ceramicines Q-T (1-4) were isolated from the barks of C. ceramicus, and their structures were determined on the basis of the 1D and 2D NMR analyses in combination with calculated 13C chemical shift data. Ceramicines Q-T (1-4) were established to be new limonoids with a cyclopentanone[α]phenanthren ring system with a ß-furyl ring at C-17, and without a tetrahydrofuran ring like ceramicine B, which is characteristic of known ceramicines. Ceramicine R (2) exhibited potent antimalarial activity against Plasmodium falciparum 3D7 strain with IC50 value of 2.8 µM.