Search Results (214)

The genus Psiadia (Asteraceae), widely distributed in Madagascar and the Mascarene Islands (Mauritius, La Réunion, Rodrigues), is traditionally used to treat bronchitis, asthma, colds, abdominal pain, and other inflammatory disorders. However, few studies have scientifically validated these traditional medicinal uses. To assess P. dentata as a valuable source of bioactive natural products, a combined ¹H NMR-based metabolomic, molecular networking, and phytochemical study was conducted. Multivariate analysis (PLS-DA) of crude extracts from Psiadia species collected on Reunion Island enabled rapid discrimination of active extracts from P. dentata and revealed two methoxylated flavonoids and one coumarin as metabolites correlated with its antiplasmodial and anti-inflammatory activities. Additionally, UHPLC-DAD-ESI-QTOF-MS/MS molecular networking approach enabled detailed chemical profiling of this species, allowing the annotation of 25 compounds (1–25) in this species. Subsequent phytochemical investigation of P. dentata leaves led to the isolation and identification of 25 metabolites, including nine new diterpenes (26–34), one new coumarin (35), and 15 known compounds (1–8, 11, 18, 19 and 36–39) from the diterpenoid, flavonoid, and coumarin families. The structures of the new compounds were elucidated using spectroscopic methods, including extensive 1D and 2D NMR and HRESIMS analyses. Biological evaluation of the isolated compounds showed that compounds 1, 7, 26 and 27 showed antiplasmodial activity against Plasmodium falciparum (3D7 strain, IC₅₀ = 7.25–13.46 μM). Compounds 7, 26, 27, 31 and 32 inhibited nitric oxide production (IC₅₀ = 0.87–27.71 μM), indicating potential anti-inflammatory effects. Only compound 1 displayed moderate cytotoxicity against HepG2 and HT29 cancer cell lines (IC₅₀ = 25.67 and 18.35 μM, respectively). Full article

In malaria-endemic regions, women remain vulnerable to Plasmodium falciparum infection at the time of delivery. However, the immunological mechanisms underlying infection-associated inflammation in primigravid women remain poorly characterized. This exploratory study investigated cytokine-based immune profiles reflecting malaria infection status at delivery. We assessed 33 primigravid women from Nanoro, Burkina Faso (mean age 19 years; range 18–20.5) at childbirth. Antibody responses to P. falciparum antigens (PfCSP, PfAMA-1, and EBA-175) and plasma levels of cytokines (IL-4, IL-10, IL-6, TNF-α, and IFN-γ) were quantified using enzyme immunoassays. Multivariate analyses, including principal component analysis (PCA) and hierarchical clustering, identified three distinct immune profiles: (1) a low-inflammatory cluster with reduced IL-6 and TNF-α, (2) a TNF-α–dominant cluster, and (3) a highly pro-inflammatory cluster with elevated IL-6 and TNF-α. Cluster stability was supported by bootstrap analysis (AU ≥ 92%). All women in the most inflammatory cluster were P. falciparum–positive at delivery (Fisher’s exact test, p = 0.04; exploratory association). These cytokine-driven profiles reflect biologically distinct inflammatory states associated with concurrent infection at delivery rather than predictive immune predispositions. The findings underscore the potential of cytokine profiling as a hypothesis-generating tool to guide future longitudinal studies on immune regulation and the postpartum period. Full article

Human African Trypanosomiasis (HAT) and Malaria are serious infectious diseases endemic in tropical regions, caused by protozoan parasites, and necessitating an urgent development of new antiprotozoal drugs. As part of our ongoing search for new antiprotozoal steroidal alkaloids from plants, we investigated the methanolic stem bark extract of Holarrhena pubescens (Apocynaceae). H. pubescens is a tropical tree that some Kenyan coastal communities have long used to treat various ailments, including fever and stomach pain. The crude extract, alkaloid fraction, and 16 subfractions acquired through centrifugal partition chromatography (CPC) displayed promising in vitro antiprotozoal activity against Trypanosoma brucei rhodesiense (Tbr) and Plasmodium falciparum (Pf). Partial least squares (PLS) regression modeling of UHPLC/+ESI QqTOF-MS data and the antiprotozoal activity data of the crude extract and its fractions was performed to predict compounds that may be responsible for the observed antiplasmodial activity. Chromatographic separation of the alkaloid fraction afforded one new steroidal alkaloid (5), along with 18 known compounds (1, 2, 4, 6–20), and one artifact (3) that was presumably formed during the acid–base extraction process. The structural characterization of the isolated compounds was accomplished using UHPLC/+ESI-QqTOF-MS/MS and NMR spectroscopy. The isolated compounds were tested for their in vitro antiprotozoal properties against the two aforementioned pathogens, as well as for their cytotoxicity against mammalian cells (L6 cell line). Compounds 2 and 16 (IC₅₀ = 0.2 μmol/L) demonstrated the highest antitrypanosomal activity, with compound 2 showing the highest selectivity (SI = 127). The new compound 5 exhibited the strongest antiplasmodial activity and selectivity against Pf (IC₅₀ = 0.7 μmol/L, SI = 43). Our findings provide further promising antiprotozoal leads for HAT and Malaria. Full article

Malaria remains a major global health burden, and the emergence of resistance to blood stage antimalarials underscores the need for new interventions targeting earlier stages of the parasite’s life cycle. The pre-erythrocytic liver stage represents a critical bottleneck and an attractive target for chemotherapeutic and prophylactic interventions. In this study, we functionally characterized the putative E3 ubiquitin ligase Trophozoite Exported Protein 1 (TEX1; PBANKA_0102200) in Plasmodium berghei using gene knockout, tagging, and imaging approaches across the mosquito and liver stages. TEX1 knockout parasites (PbTEX1-KO) showed impaired development during mosquito-stage transitions, with significant reductions in ookinete formation, oocyst numbers, and sporozoites reaching the salivary glands. In hepatic stages, TEX1-KO parasites displayed reduced growth, abnormal nuclear division, and impaired liver stage maturation, ultimately leading to a dramatic decline in detached cell formation and blood stage infectivity. Endogenous C-terminal tagging of TEX1 with GFP and 3×HA revealed a discrete subnuclear localization pattern, indicating a critical role in DNA synthesis and/or mitotic regulation. Our findings reveal that TEX1 is required for nuclear replication and division and successful development in both the mosquito and liver stages of Plasmodium. Given its pivotal role and nuclear localization during hepatic schizogony, TEX1 represents a promising target for the development of liver stage antimalarial interventions. Full article

Background: Thymol, a natural phenol with antimicrobial and antioxidant activities, and its derivatives offer promising scaffolds for antimalarial drug development, potentially helping overcome resistance. Materials and Methods: In this study, thymol derivatives were synthesized and assessed as antiplasmodial agents against both resistant and sensitive strains of P. falciparum, as well as Plasmodium knowlesi. The ligand molecules were assessed with Plasmodium falciparum chloroquine resistance transporter (PfCRT)’s potential using in silico molecular docking and ADMET analysis. The parent compound, thymol, was chemically modified through esterification and conjugation with hydroxybenzoic acid and cinnamic acid derivatives to generate analogs with varied substitution patterns. Results: The findings showed that among seven successfully synthesized thymol derivatives, compounds 4 and 6 exhibited notable potency against Plasmodium falciparum 3D7 (EC₅₀ = 6.01 ± 1.7 µM and 6.8 ± 1.1 µM, respectively) with high SI values (16.5 and 14.6, respectively), indicating improved selectivity relative to thymol. The cytotoxicity evaluation against HCF mammalian cells revealed that most thymol derivatives were non-toxic, with CC₅₀ values greater than 99 µM, except for compound 3 (CC₅₀ = 71.4 ± 4.5 µM) and compound 1 (CC₅₀ = 58.4 ± 2.3 µM), which exhibited moderate cytotoxic effects. The molecular docking results showed that compounds 3 (−8.4 kcal/mol), 4 (−8.3 kcal/mol), and 6 (−8.3 kcal/mol) exhibited strong binding affinities toward the PfCRT protein. Conclusions: Therefore, thymol derivative compounds 4 and 6 exhibited stronger antiplasmodial activity in vitro against P. falciparum and P. knowlesi with safety profiles against mammalian cells, targeting PfCRT, highlighting their potential as lead antimalarial candidates. Full article

Given the known biological activity of both natural and synthetic substituted 1H-phenalen-1-ones, the generation of a small chemically and structurally diverse 1H-phenalen-1-one-based library of compounds was warranted. Herein, we have synthesized several groups of compounds to broaden and improve the chemical diversity of our 1H-phenalen-1-one collection. Additionally, we have also introduced hydroxyl, amides or carboxylic groups onto the core, or nitrogen atoms into the core, to increase the chemical diversity while also lowering the ClogP values to aid their water solubility. Notably, we have also improved the synthetic routes to several compounds of interest and have observed the unexpected formation of phenoxazine and acridin-7-one systems during cross-coupling reactions with polyfunctional anilines. Combining the compounds generated in this work with previous ones has enabled us to create a library of chemically diverse 1H-phenalen-1-one available for screening assays. Evaluation of anti-plasmodial activity against the chloroquine-resistant Plasmodium falciparum strain FCR3 revealed four compounds with notable activity, three of which exhibited IC₅₀ values below 1 µM, while none displayed significant cytotoxicity at 10 µM. Full article

The 26S proteasome is the main proteolytic machinery involved in protein degradation, thereby contributing to the homeostasis and stress response of eukaryotic cells. This macromolecular complex consists of a 20S core particle assembled with one or two 19S regulatory particles. Here, we describe the Plasmodium berghei (Pb) proteasome AAA-ATPase regulatory subunit Rpt3 and demonstrate its binding to the Protein Phosphatase 1 catalytic subunit (PP1c), which is one of the major and essential parasite phosphatases. The PbRpt3 protein enhances the activity of PP1c both in vitro and in a Xenopus oocyte heterologous model. Further investigation of this model suggests that the PbRpt3-PP1c interaction may occur outside of the proteasome, and it reveals that the RVxF motifs of PbRpt3 are involved in its binding and regulatory function. Moreover, the ATP-binding capacity of PbRpt3 may also contribute to its phosphatase regulatory activity. In the parasite, reverse genetic studies suggest an essential role for PbRpt3 during erythrocytic cycle of P. berghei, and an interactome analysis confirmed that PbRpt3 belongs to the 19S regulatory particle of the proteasome and may interact with proteins previously shown to be involved in phospholipid binding. Full article

Human African Trypanosomiasis (HAT; sleeping sickness) and Malaria are life-threatening protozoan infections in tropical regions, with limited treatment options. As part of our ongoing efforts to discover new aminosteroid alkaloids from the Buxaceae family with antiprotozoal activity, which might serve as leads to new drugs against these infections, we investigated the dichloromethane extract from the leaves of Buxus obtusifolia (Mildbr.) Hutch. collected in Kenya, a species native to Kenya and Tanzania. To the best of our knowledge, and based on the most recent comprehensive literature review, this study represents the first phytochemical investigation of this plant. The alkaloid-enriched fraction yielded a total of 24 aminosteroid alkaloids, including 18 hitherto undescribed compounds (2, 3, 5–9, 11, 12, 15–19, and 21–24), along with six known compounds, two of which (1 and 4) are described as constituents of a natural source for the first time. Obtusiaminocyclin (24) represents the first Buxus alkaloid with a novel carbocyclic steroid skeleton with a cyclopropane ring comprising C-9, C-19 and C-11 accompanied by an unprecedented amino bridge between C-3 and C-10. The structures of the isolated compounds were determined using UHPLC/+ESI-QqTOF-MS/MS and NMR spectroscopy. The total crude extract, the alkaloid-enriched fraction, CPC subfractions and all isolated compounds were tested for in vitro antiprotozoal activity against Trypanosoma brucei rhodesiense (Tbr, responsible for East African HAT) and Plasmodium falciparum (Pf, responsible for tropical Malaria) as well as cytotoxicity against mammalian cells (L6 cell line). Deoxycyclovirobuxeine-B (12) (IC₅₀ = 0.8 µmol/L, SI = 108) and 29-trimethoxybenzoyloxy-obtusibuxoline (5) (IC₅₀ = 0.5 µmol/L, SI = 11) showed the highest activities with good selectivity indices against Tbr and Pf, respectively. Consequently, our findings provide valuable aminosteroid candidates that can serve as promising leads in our ongoing search for new drugs against HAT and Malaria. Full article

Background/Objectives: In the Brazilian Amazon, which accounts for over 99% of national malaria cases, 34,260 cases were reported as of August 2025, predominantly caused by Plasmodium vivax, responsible for 86.69% of the infections. The increasing resistance of the parasite to conventional therapies highlights the urgent need for novel control strategies, with essential oils and plant-derived substances emerging as promising alternatives. Methods: In this context, we evaluated the anti-Plasmodium potential of Piper alatipetiolatum essential oil and its major constituent 6-ishwarone against P. vivax, including cytotoxicity in Vero and PBMCs, molecular docking on dihydrofolate reductase (DHFR) and lactate dehydrogenase (LDH), and in silico pharmacokinetic profiling. Results: Both the oil and 6-ishwarone inhibited P. vivax dose-dependently (2.1 ± 1 to 100%), with IC₅₀ values of 9.25 µg/mL and 3.93 µg/mL, respectively. Importantly, no cytotoxic effects were observed at 24 h, with cell viability ranging from 94.7% to 98.3%, highlighting the selectivity of these compounds towards the parasite over mammalian cells. Docking studies indicated selective binding of 6-ishwarone to DHFR (−7.7 kcal/mol; Ki = 2.27 µM) with key interactions (Trp816, Lys820, Tyr819, Asn823, Thr865), whereas binding to LDH was weaker (−6.2 kcal/mol; Ki = 28.10 µM), suggesting DHFR as the primary molecular target. In silico ADMET predictions and experimental data indicated favorable drug-like properties: TPSA = 20.23 Ų, moderate lipophilicity (LogP = 3.37), soluble (ESOL Log S = −3.58; Ali Log S = −3.89; Silicos-IT Log S = −2.84), high gastrointestinal absorption, BBB permeability (0.985), not a P-glycoprotein substrate (0.11), and low likelihood of CYP inhibition. Toxicity predictions showed non-mutagenic and non-hepatotoxic effects, low cardiotoxicity (hERG inhibition risk 0.08–0.32), low reproductive toxicity (0.03), moderate neurotoxicity (0.28), low acute toxicity (oral LD₅₀ = 2.061 mol/kg), and low chronic toxicity (LOAEL = 1.995 log mg/kg/day). Conclusions: Together, these findings demonstrate that essential oil and 6-ishwarone of P. alatipetiolatum are selective, bioavailable, and promising natural leads for antimalarial drug development. Full article

The naphthoquinone skeleton is known for broad biological applications and, in particular, for antiparasitic efficacy. As part of our ongoing search for new antiprotozoal naphthoquinone derivatives, we incorporated computer-aided optimization models utilizing physicochemical parameters into our approach. Herein, we report on the synthesis of 21 new benzamido–menadione and naphthoquinone derivatives via the Kochi–Anderson reaction. The antiprotozoal activity of all the synthesized compounds was evaluated against Plasmodium falciparum NF54 and Trypanosoma brucei rhodesiense STIB900. Cytotoxicity towards L6 cells was also determined, and the respective selectivity indices (SI) were calculated. Several ligand efficiency metrics, such as LLE, SILE, and FQ, were calculated, and the results were visualized in scatterplots. Almost all of the synthesized benzamido–menadione derivatives exhibited high activity against NF54 (IC₅₀ < 1 µM), with the strongest activity and excellent selectivity observed in the 2-fluoro-5-trifluoromethylbenzamido derivative 2f (IC₅₀ = 0.021 µM, SI = 10,000). Specific ligand efficiency metrics, such as SILE, LLE or FQ, showed a clear correlation with the corresponding antiplasmodial activities. Toxicity predictions confirmed low acute oral toxicity for most compounds, further supporting their potential as safe drug candidates. Our findings highlight the benzamido–menadione scaffold as a viable option for new antiplasmodial drugs. Full article

The present work reports the bioguided isolation of constituents from the ethanol extract of Holarrhena floribunda stem bark, their identification by UHPLC-ESI-QTOF-MS/MS identification, and the in silico prediction of the pharmacokinetic and toxicity parameters. The crude extract, along with its n-hexane and alkaloid-rich fractions, displayed moderate to good antiplasmodial activity in vitro against chloroquine-sensitive (3D7) and multidrug-resistant (Dd2) strains of Plasmodium falciparum, with IC₅₀ values ranging from 6.54 to 43.54 µg/mL. Seventeen steroidal alkaloids (1–17) were identified in the most active fraction using UHPLC-ESI-QTOF-MS/MS, based on their fragmentation patterns and analysis with the Structural Similarity Network Annotation Platform for Mass Spectrometry (SNAP-MS). Furthermore, bioguided isolation of the ethanol extract yielded twenty-one compounds (3, 5, 10, 14–16, 18–31), whose structures were elucidated by spectroscopic methods. Among them, compounds 5, 14, and 27 showed the highest potency against the two strains of P. falciparum, with IC₅₀ values between 25.97 and 55.78 µM. In addition, the in silico prediction of pharmacokinetic parameters and drug-likeness using the SwissADME web tool indicated that most of the evaluated compounds (1, 3–5, and 14–16) complied with Lipinski’s rule of five. Full article

Pachysandra terminalis (P. terminalis), a plant belonging to the Buxaceae family, is known as a great source of aminosteroid alkaloids. In a previous communication, we reported on the isolation of a variety of aminosteroids from P. terminalis, which presented interesting activity against the protozoan pathogens, Trypanosoma brucei rhodesiense and Plasmodium falciparum. In the present study, variations in the alkaloid profile of P. terminalis related to seasonal changes as well as differences between plant organs (leaves and twigs) and between plant populations were investigated to prioritize candidates for targeted isolation in further studies. For this purpose, sample material of P. terminalis was collected from the two nearby populations in monthly intervals over one year. The ethanolic (75%) extracts were analyzed using UHPLC/+ESI-QqTOF-MS/MS, and the resulting data converted to variables encoding the intensity of MS signals in particular m/z and retention time (t_R) intervals over the chromatographic runs. The very large and complex data matrix of these <t_R:m/z> variables was evaluated using multivariate data analysis, especially principal component analysis (PCA) and volcano plot analysis of t-test data. The results of these analyses, for the first time, allowed a holistic analysis of variation in the alkaloid profiles in P. terminalis organs over the vegetation period. The evaluation of the PCA scores and loadings plots of principal components 1 through 3, as well as of volcano plots, highlighted 25 different compounds, mostly identified as aminosteroid alkaloids, that were most relevant for the differences between leaves and twigs and between the two populations and mainly determined the changes in their chemical profiles over the vegetation period. Full article

Understanding Plasmodium falciparum population genetic diversity is crucial to assess the impact of malaria control interventions. This study investigated P. falciparum genetic diversity using merozoite surface protein 1 (msp1), msp2 and glutamate-rich protein (glurp) in Korhogo district, Northern Côte d’Ivoire. DNA was extracted from dried blood spots (DBSs) collected in the health district of Korhogo between 2019 and 2020. The msp1, msp2, and glurp genes were amplified by polymerase chain reaction (PCR), and amplicon sizes were determined by capillary electrophoresis. Out of 179 samples randomly selected and genotyped, 82% were successfully amplified for msp1, 85% for msp2, and 75% for glurp. For msp1, the K1 allelic family had 20 genotypes, MAD20 had 23, and RO33 had only one genotype. For msp2, there were 59 and 33 genotypes for 3D7 and FC27, respectively, and for glurp, 45 genotypes were detected. The parasite population was highly diverse with an expected heterozygosity (H_E) of ≥0.9 for all 3 markers. Our study showed high genetic diversity of msp1, msp2, and glurp in P. falciparum isolates from Korhogo district, Northern Côte d’Ivoire. These data could provide baseline information on P. falciparum genetic diversity for further epidemiological studies, needed to assess interventions implemented in this area. Full article

The study of various microorganisms isolated from an Indian Ocean sponge, Scopalina hapalia ML-263, led to the selection of a promising Actinobacteria strain, Micromonospora sp. SH-82. Genomic analysis identified this strain as a new species, revealing the presence of 23 biosynthetic gene clusters (BGCs), some of which are associated with the synthesis of specialized metabolites such as polyketides deriving from polyketide synthases (PKSs). The strain was cultivated under favorable conditions for the production of bioactive molecules, resulting in the isolation and identification of seven microbial metabolites. Three of them are potentially novel, two erythronolides and one erythromycin, all characterized by a rare C10–C11 double bond. Some of these compounds also display atypical conformations, forming hemiacetals or spiroacetals. Their identification was achieved through detailed chemical analyses (NMR and ESI⁺-HRMS). A molecular networking approach was employed to assess the presence of potentially novel molecules in the microbial crude extract, supported by the identification of isolated molecules. Four molecules (1, 2, 3 and 5) were evaluated for their cytotoxic activities against cancer cell lines (HCT-116 and MDA-MB-231) and the immortalized retinal pigment epithelial RPE1 cells. No activity was observed in the latter, suggesting a lack of toxicity toward healthy cells. Moreover, megalomicin C1 (3), one of the isolated compounds, showed interesting antiplasmodial activity against Plasmodium falciparum 3D7, with an IC₅₀ of 6.37 ± 2.99 µM. Full article

In Brazil, Plasmodium infections in non-human primates (NHPs) have been associated with P. simium and P. brasilianum, which are morphologically and genetically similar to the human-infecting species P. vivax and P. malariae, respectively. Surveillance and monitoring of wild NHPs are crucial for understanding the distribution of these parasites and assessing the risk of zoonotic transmission. This study aimed to detect the presence of Plasmodium spp. genetic material in Platyrrhini primates from 47 municipalities in the states of Bahia and Minas Gerais. The animals were captured using Tomahawk-type live traps baited with fruit or immobilized with tranquilizer darts. Free-ranging individuals were chemically restrained via inhalation anesthesia using VetBag^® or intramuscular anesthesia injection. Blood samples were collected from the femoral vein. A total of 298 blood and tissue samples were collected from 10 primate species across five genera: Alouatta caraya (25), Alouatta guariba clamitans (1), Callicebus melanochir (1), Callithrix geoffroyi (28), Callithrix jacchus (4), Callithrix kuhlii (31), Callithrix penicillata (175), Callithrix spp. hybrids (15), Leontopithecus chrysomelas (16), Sapajus robustus (1), and Sapajus xanthosthernos (1). Molecular diagnosis was performed using a nested PCR targeting the 18S small subunit ribosomal RNA (18S SSU rRNA) gene, followed by sequencing. Of the 298 samples analyzed, only one (0.3%) from Bahia tested positive for Plasmodium brasilianum/P. malariae. This represents the first detection of this parasite in a free-living C. geoffroyi in Brazil. These findings highlight the importance of continued surveillance of Plasmodium infections in NHPs to identify regions at risk for zoonotic transmission. Full article