Plasmodium falciparum Glutamic Acid-Rich Protein-Independent Polyclonal Antibodies Inhibit Malaria Parasite Growth in Human Erythrocytes.

Plasmodium falciparum glutamic acid-rich protein (PfGARP) is a recently characterized cell surface antigen encoded by Plasmodium falciparum, the causative agent of severe human malaria pathophysiology. Previously, we reported that the human erythrocyte band 3 (SLC4A1) serves as a host receptor for PfGARP. Antibodies against PfGARP did not affect parasite invasion and growth. We surmised that PfGARP may play a role in the rosetting and adhesion of malaria. Another study reported that antibodies targeting PfGARP exhibit potent inhibition of parasite growth. This inhibition occurred without the presence of any immune or complement components, suggesting the activation of an inherent density-dependent regulatory system. Here, we used polyclonal antibodies against PfGARP and a monoclonal antibody mAb7899 to demonstrate that anti-PfGARP polyclonal antibodies, but not mAb7899, exerted potent inhibition of parasite growth in infected erythrocytes independent of PfGARP. These findings suggest that an unknown malaria protein(s) is the target of growth arrest by polyclonal antibodies raised against PfGARP.

In vitro and in vivo efficacy of the amiodarone and praziquantel combination against the blood fluke Schistosoma mansoni.

Schistosomiasis, a widespread parasitic disease caused by the blood fluke of the genus Schistosoma, affects over 230 million people, primarily in developing countries. Praziquantel, the sole drug currently approved for schistosomiasis treatment, demonstrates effectiveness against patent infections. A recent study highlighted the antiparasitic properties of amiodarone, an anti-arrhythmic drug, exhibiting higher efficacy than praziquantel against prepatent infections. This study assessed the efficacy of amiodarone and praziquantel, both individually and in combination, against Schistosoma mansoni through comprehensive in vitro and in vivo experiments. In vitro experiments demonstrated synergistic activity (fractional inhibitory concentration index ≤0.5) for combinations of amiodarone with praziquantel. In a murine model of schistosomiasis featuring prepatent infections, treatments involving amiodarone (200 or 400 mg/kg) followed by praziquantel (200 or 400 mg/kg) yielded a substantial reduction in worm burden (60%-70%). Given the low efficacy of praziquantel in prepatent infections, combinations of amiodarone with praziquantel may offer clinical utility in the treatment of schistosomiasis.

In vitro efficacy of next-generation dihydrotriazines and biguanides against babesiosis and malaria parasites.

Babesia and Plasmodium pathogens, the causative agents of babesiosis and malaria, are vector-borne intraerythrocytic protozoan parasites, posing significant threats to both human and animal health. The widespread resistance exhibited by these pathogens to various classes of antiparasitic drugs underscores the need for the development of novel and more effective therapeutic strategies. Antifolates have long been recognized as attractive antiparasitic drugs as they target the folate pathway, which is essential for the biosynthesis of purines and pyrimidines, and thus is vital for the survival and proliferation of protozoan parasites. More efficacious and safer analogs within this class are needed to overcome challenges due to resistance to commonly used antifolates, such as pyrimethamine, and to address liabilities associated with the dihydrotriazines, WR99210 and JPC-2067. Here, we utilized an in vitro culture condition suitable for the continuous propagation of Babesia duncani, Babesia divergens, Babesia MO1, and Plasmodium falciparum in human erythrocytes to screen a library of 50 dihydrotriazines and 29 biguanides for their efficacy in vitro and compared their potency and therapeutic indices across different species and isolates. We identified nine analogs that inhibit the growth of all species, including the P. falciparum pyrimethamine-resistant strain HB3, with IC50 values below 10 nM, and display excellent in vitro therapeutic indices. These compounds hold substantial promise as lead antifolates for further development as broad-spectrum antiparasitic drugs.

Novel 4-[4-(4-methylpiperazin-1-yl)phenyl]-6-arylpyrimidine derivatives and their antitrypanosomal activities against T.brucei.

Human African trypanosomiasis, or sleeping sickness, is a neglected tropical disease caused by Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense and is invariably fatal unless treated. Current therapies present limitations in their application, parasite resistance, or require further clinical investigation for wider use. Our work, informed by previous findings, presents novel 4-[4-(4-methylpiperazin-1-yl)phenyl]-6-arylpyrimidine derivatives with promising antitrypanosomal activity. In particular, 32 exhibits an in vitro EC50 value of 0.5 µM against Trypanosoma brucei rhodesiense, and analogues 29, 30 and 33 show antitrypanosomal activities in the <1 µM range. We have demonstrated that substituted 4-[4-(4-methylpiperazin-1-yl)phenyl]-6-arylpyrimidines present promising antitrypanosomal hit molecules with potential for further preclinical development.

Catechol compounds as dual-targeting agents for fish protection against Ichthyophthirius multifiliis infections.

Aquaculture is one of the fastest growing sectors in global food production, recognized as a significant contributor to poverty alleviation, food security, and income generation. However, the frequent occurrence of diseases caused by pathogen infections result in reduced yields and economic losses, posing a substantial constraint to the sustainable development of aquaculture. Here, our study identified that four catechol compounds, quercetin, luteolin, caffeic acid, and chlorogenic acid, exhibited potent antiparasitic effects against Ichthyophthirius multifiliis in both, in vitro and in vivo. The parasite is recognized as one of the most pathogenic to fish worldwide. Using a combination of in silico methods, the dipeptidyl peptidase (DPP) was identified as a critical target for catechol compounds. The two hydroxyl radicals of the catechol group were essential for its binding to and interacting with the DPP protein. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that catechol compounds disrupt pathways associated with the metabolism and growth of I. multifiliis, thereby exerting antiparasitic effects. Furthermore, these compounds attenuated the expression of proinflammatory cytokines in vivo in fish and promoted macrophage polarization toward M2 phenotype by inhibiting the STAT1 signaling pathway. The dual activity of catechol compounds, acting as both direct antiparasitic and anti-inflammatory agents in fish, offers a promising therapeutic approach for combating I. multifiliis infections in aquaculture.

Investigation of antileishmanial, antioxidant activities, CT-DNA interaction and DFT study of novel cobalt(II) complexes derived from mesogenic aromatic amino acids based Schiff base ligands.

In the present work, new Co(II) complexes were synthesized from mesogenic aromatic amino acids based Schiff base ligands, HL1 [Methyl 2-((2-hydroxy-4-(tetradecyloxy)benzylidene)amino)-3-phenylpropanoate] and HL2 [Methyl 2-((2-hydroxy-4-(tetradecyloxy)benzylidene)amino)-3-(1H-indol-2-yl)propanoate]. The compounds were thoroughly characterised using different elemental, thermogravimetric and spectroscopic studies. The in-vitro antileishmanial efficacy of the compounds against Leishmania donovani was evaluated by MTT assay and the antioxidant activity was performed by Mensor's method. The cell viability percentage and IC50 values for both the antileishmanial and antioxidant studies revealed that the cobalt(II) complexes are comparable to the standard, amphotericin B and ascorbic acid, respectively, signifying the potential applications of the biogenic compounds. The CT-DNA interaction experiments study using photophysical techniques indicated that the cobalt(II) complexes exhibited pronounced interactions as compared to the parent ligand. The parent ligands were found to possess mesogenicity as evidenced from the polarizing optical microscope (POM) and differential scanning calorimetry (DSC). The optical band gap of the compounds, as estimated from the Tauc plot of the UV-Vis spectra, lies within the domain of optoelectronic material properties, which was further supported through Density Functional Theory (DFT) study. Moreover, DFT methods have been used to explore the ground state geometry and DFT based reactivity descriptors of the two synthesised ligands, HL1 and HL2 along with their corresponding Co(II) complexes, Co(L1)2 and Co(L2)2. Reactivity descriptors obtained from Conceptual Density Functional Theory (CDFT) analysis reveal that Co(L1)2 is the most stable and Co(L2)2 is the most electrophilic.

Tubulin inhibitors. Selected scaffolds and main trends in the design of novel anticancer and antiparasitic agents.

Design of tubulin inhibitors as anticancer drugs dynamically developed over the past 20 years. The modern arsenal of potential tubulin-targeting anticancer agents is represented by small molecules, monoclonal antibodies, and antibody-drug conjugates. Moreover, targeting tubulin has been a successful strategy in the development of antiparasitic drugs. In the present review, an overall picture of the research and development of potential tubulin-targeting agents using small molecules between 2018 and 2023 is provided. The data about some most often used and prospective chemotypes of small molecules (privileged heterocycles, moieties of natural molecules) and synthetic methodologies (analogue-based, fragment-based drug design, molecular hybridization) applied for the design of novel agents with an impact on the tubulin system are summarized. The design and prospects of multi-target agents with an impact on the tubulin system were also highlighted. Reported in the review data contribute to the "structure-activity" profile of tubulin-targeting small molecules as anticancer and antiparasitic agents and will be useful for the application by medicinal chemists in further exploration, design, improvement, and optimization of this class of molecules.

First insights on the susceptibility of native coccidicidal fungi Mucor circinelloides and Mucor lusitanicus to different avian antiparasitic drugs.

BACKGROUND: The combined application of predatory fungi and antiparasitic drugs is a sustainable approach for the integrated control of animal gastrointestinal (GI) parasites. However, literature addressing the possible interference of antiparasitic drugs on the performance of these fungi is still scarce. This research aimed to assess the in vitro susceptibility of six native coccidicidal fungi isolates of the species Mucor circinelloides and one Mucor lusitanicus isolate to several antiparasitic drugs commonly used to treat GI parasites' infections in birds, namely anthelminthics such as Albendazole, Fenbendazole, Levamisole and Ivermectin, and anticoccidials such as Lasalocid, Amprolium and Toltrazuril (drug concentrations of 0.0078-4 µg/mL), using 96-well microplates filled with RPMI 1640 medium, and also on Sabouraud Agar (SA). RESULTS: This research revealed that the exposition of all Mucor isolates to the tested anthelminthic and anticoccidial drug concentrations did not inhibit their growth. Fungal growth was recorded in RPMI medium, after 48 h of drug exposure, as well as on SA medium after exposure to the maximum drug concentration. CONCLUSIONS: Preliminary findings from this research suggest the potential compatibility of these Mucor isolates with antiparasitic drugs for the integrated control of avian intestinal parasites. However, further in vitro and in vivo studies are needed to confirm this hypothesis.

Therapeutic applications of carbohydrate-based compounds: a sweet solution for medical advancement.

Carbohydrates, one of the most abundant biomolecules found in nature, have been seen traditionally as a dietary component of foods. Recent findings, however, have unveiled their medicinal potential in the form of carbohydrates-derived drugs. Their remarkable structural diversity, high optical purity, bioavailability, low toxicity and the presence of multiple functional groups have positioned them as a valuable scaffold and an exciting frontier in contemporary therapeutics. At present, more than 170 carbohydrates-based therapeutics have been granted approval by varying regulatory agencies such as United States Food and Drug Administration (FDA), Japan Pharmaceuticals and Medical Devices Agency (PMDA), Chinese National Medical Products Administration (NMPA), and the European Medicines Agency (EMA). This article explores an overview of the fascinating potential and impact of carbohydrate-derived compounds as pharmacological agents and drug delivery vehicles.

Potent hydroxamate-derived compounds arrest endodyogeny of Toxoplasma gondii tachyzoites.

Toxoplasmosis is a zoonosis that is a worldwide health problem, commonly affecting fetal development and immunodeficient patients. Treatment is carried out with a combination of pyrimethamine and sulfadiazine, which can cause cytopenia and intolerance and does not lead to a parasitological cure of the infection. Lysine deacetylases (KDACs), which remove an acetyl group from lysine residues in histone and non-histone proteins are found in the Toxoplasma gondii genome. Previous work showed the hydroxamate-type KDAC inhibitors Tubastatin A (TST) and Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) were effective against T. gondii. In the present study, the effects of three hydroxamates (KV-24, KV-30, KV-46), which were originally designed to inhibit human KDAC6, showed different effects against T. gondii. These compounds contain a heterocyclic cap group and a benzyl linker bearing the hydroxamic acid group in para-position. All compounds showed selective activity against T. gondii proliferation, inhibiting tachyzoite proliferation with IC50 values in a nanomolar range after 48h treatment. Microscopy analyses showed that after treatment, tachyzoites presented mislocalization of the apicoplast, disorganization of the inner membrane complex, and arrest in the completion of new daughter cells. The number of dividing cells with incomplete endodyogeny increased significantly after treatment, indicating the compounds can interfere in the late steps of cell division. The results obtained in this work that these new hydroxamates should be considered for future in vivo tests and the development of new compounds for treating toxoplasmosis.

Activity of pyridyl-pyrazolone derivatives against Trypanosoma cruzi.

New affordable drugs are needed for the treatment of infection with the protozoan parasite Trypanosoma cruzi responsible for the Chagas disease (CD). Only two old drugs are currently available, nifurtimox and benznidazole (Bz) but they exhibit unwanted side effects and display a weak activity in the late chronic phase of the disease. In this context, we evaluated the activity of a series of aryl-pyrazolone derivatives against T cruzi, using both bloodstream trypomastigote and intracellular amastigote forms of the parasite. The test compounds originate from a series of anticancer agents targeting the immune checkpoint ligand PD-L1 and bear an analogy with known anti-trypanosomal pyrazolones. A first group of 6 phenyl-pyrazolones was tested, revealing the activity of a single pyridyl-pyrazolone derivative. Then a second group of 8 compounds with a common pyridyl-pyrazolone core was evaluated. The in vitro testing process led to the identification of two non-cytotoxic and highly potent molecules against the intracellular form of T. cruzi, with an activity comparable to Bz. Moreover, one compound revealed an activity largely superior to that of Bz against bloodstream trypomastigotes, while being non-cytotoxic (selectivity index >1000). Unfortunately, the compound showed little activity in vivo, most likely due to its very limited plasma stability. However, the study opens novel perspectives for the design of new anti-trypanosomal products and the mechanism of action of the compounds is discussed.

Massive neurocysticercosis in a ten-year-old girl: a case report.

BACKGROUND: Massive neurocysticercosis is a rare form of neurocysticercosis, and can lead to serious conditions and even death. CASE PRESENTATION: Here we present a case of ten-year-old Tibetan girl who developed headache and vomiting. Her brain magnetic resonance imaging (MRI) illustrated lots of intracranial cystic lesions, and no obvious extracranial lesions were found. Serum immunoglobulin G antibodies against cysticerci were positive by the use of an enzyme-linked immunosorbent assay (ELISA). These results in combination with her medical history were in line with massive neurocysticercosis. The patients recovered well after supportive management and antiparasitic treatment. CONCLUSIONS: This case provides insights on the diagnosis and treatment of massive neurocysticercosis. The treatment of patients with massive neurocysticercosis should be in an individualized fashion, and the use of antiparasitic drugs in these patients must be decided after carefully weighing the risks and benefits.

Exploring the use of fatty acid ethyl esters as a potential natural solution for the treatment of fish parasitic diseases.

Alternatives to conventional chemical treatments for parasitic diseases in fish are needed. Microalgal-sourced fatty acid ethyl esters (FAEEs) have shown an antiparasitic effect against Gyrodactylus turnbulli infection in guppies. Here, we tested a range of commercial FAEEs of various carbon chain lengths and unsaturation levels against two fish parasites. Guppies and barramundi infected with G. turnbulli and Trichodina sp., respectively, were used. The most effective FAEE, after excluding those toxic to fish, was ethyl laurate (12:0). For both parasites, the LD50 was 18.75 µM within 250 min of incubation. Ethyl eicosapentaenoate (20:5n3) was the next most effective FAEE against G. turnbulli, and dihomo-γ-linolenic acid ethyl ester (20:3n6) and ethyl α-linolenate (18:3n3) were the next most effective against Trichodina sp. In addition, FAEEs prepared from the microalga Phaeodactylum tricornutum residue, after fucoxanthin extraction, were examined against Trichodina sp. infection in barramundi for the first time. LD85 and LD100 was achieved at 2.5 and 5 µL mL-1 of the FAEE preparation, respectively. In vivo, immersion of infected barramundi in 1.25 µL mL-1 of this preparation for 24 h reduced infection prevalence from 100% to 53% and was non-toxic to fish.

Synthesis and evaluation of febrifugine derivatives as anticoccidial agents.

A series of new febrifugine derivatives with a 4(3H)-quinazolinone scaffold were synthesized and evaluated for their anticoccidial activity both in vitro and in vivo. The targets' in vitro activity against Eimeria tenella was studied using quantitative real-time reverse transcription polymerase chain reaction and Madin-Darby bovine kidney cells. Most of these compounds demonstrated anticoccidial efficacy, with inhibition ratios ranging from 3.3% to 85.7%. Specifically, compounds 33 and 34 showed significant inhibitory effects on the proliferation of E. tenella and exhibited lower cytotoxicity compared to febrifugine. The IC50 values of compounds 33 and 34 were 3.48 and 1.79 µM, respectively, while the CC50 values were >100 µM for both compounds. Furthermore, in a study involving 14-day-old chickens infected with 5 × 104 sporulated oocysts, treatment with five selected compounds (22, 24, 28, 33, and 34), which exhibited in vitro inhibition rate of over 50% at 100 µM, at a dose of 40 mg/kg in daily feed for 8 consecutive days showed that compound 34 possessed moderate in vivo activity against coccidiosis, with an anticoccidial index of 164. Structure-activity relationship studies suggested that spirocyclic piperidine may be a preferable substructure to maintain high effectiveness in inhibiting Eimeria spp., when the side chain 1-(3-hydroxypiperidin-2-yl)propan-2-one was replaced.

Green Synthesis of Uncoated and Olive Leaf Extract-Coated Silver Nanoparticles: Sunlight Photocatalytic, Antiparasitic, and Antifungal Activities.

The circular economy, which attempts to decrease agricultural waste while also improving sustainable development through the production of sustainable products from waste and by-products, is currently one of the main objectives of environmental research. Taking this view, this study used a green approach to synthesize two forms of silver nanoparticles: coated silver nanoparticles with olive leaf extract (Ag-olive) and uncoated pure silver nanoparticles (Ag-pure), which were produced by the calcination of Ag-olive at 550 °C. The extract and the fabricated nanoparticles were characterized by a variety of physicochemical techniques, including high-performance liquid chromatography (HPLC), thermal gravimetric analysis (TGA), X-ray diffraction (XRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Adult ticks (Hyalomma dromedarii) (Acari: Ixodidae) were used in this study to evaluate the antiparasitic activity of synthesized nanoparticles and extract. Furthermore, the antifungal activity was evaluated against Aspergillus aculeatus strain N (MW958085), Fuserium oxysporum (MT550034), and Alternaria tenuissiuma (MT550036). In both antiparasitic and antifungal tests, the as-synthesized Ag-olive showed higher inhibition activity than Ag-pure and olive leaf extract. The findings of this research suggest that Ag-olive may be a powerful and eco-friendly antiparasitic and antifungal agent. Ag-pure was also evaluated as a photocatalyst under sunlight for the detoxification of Eri-chrome-black T (EBT), methylene blue (MB), methyl orange (MO), and rhodamine B (RhB).

Design and Synthesis of 1,3-Diarylpyrazoles and Investigation of Their Cytotoxicity and Antiparasitic Profile.

Herein, we report a series of 1,3-diarylpyrazoles that are analogues of compound 26/HIT 8. We previously identified this molecule as a 'hit' during a high-throughput screening campaign for autophagy inducers. A variety of synthetic strategies were utilized to modify the 1,3-diarylpyrazole core at its 1-, 3-, and 4-position. Compounds were assessed in vitro to identify their cytotoxicity properties. Of note, several compounds in the series displayed relevant cytotoxicity, which warrants scrutiny while interpreting biological activities that have been reported for structurally related molecules. In addition, antiparasitic activities were recorded against a range of human-infective protozoa, including Trypanosoma cruzi, T. brucei rhodesiense, and Leishmania infantum. The most interesting compounds displayed low micromolar whole-cell potencies against individual or several parasitic species, while lacking cytotoxicity against human cells.

The Synthesis of 2'-Hydroxychalcones under Ball Mill Conditions and Their Biological Activities.

Chalcones are polyphenols that belong to the flavonoids family, known for their broad pharmacological properties. They have thus attracted the attention of chemists for their obtention and potential activities. In our study, a library of compounds from 2'-hydroxychalcone's family was first synthesized. A one-step mechanochemical synthesis via Claisen-Schmidt condensation reaction under ball mill conditions was studied, first in a model reaction between a 5'-fluoro-2'-hydroxyacetophenone and 3,4-dimethoxybenzaldehyde. The reaction was optimized in terms of catalysts, ratio of reagents, reaction time, and influence of additives. Among all assays, we retained the best one, which gave the highest yield of 96% when operating in the presence of 1 + 1 eq. of substituted benzaldehyde and 2 eq. of KOH under two grinding cycles of 30 min. Thus, this protocol was adopted for the synthesis of the selected library of 2'-hydroxychalcones derivatives. The biological activities of 17 compounds were then assessed against Plasmodium falciparum, Leishmania donovani parasite development, as well as IGR-39 melanoma cell lines by inhibiting their viability and proliferation. Compounds 6 and 11 are the most potent against L. donovani, exhibiting IC50 values of 2.33 µM and 2.82 µM, respectively, better than the reference drug Miltefosine (3.66 µM). Compound 15 presented the most interesting antimalarial activity against the 3D7 strain, with IC50 = 3.21 µM. Finally, chalcone 12 gave the best result against IGR-39 melanoma cell lines, with an IC50 value of 12 µM better than the reference drug Dacarbazine (IC50 = 25 µM).

Review on the Applications of Selected Metal-Based Complexes on Infectious Diseases.

Fatalities caused by infectious diseases (i.e., diseases caused by parasite, bacteria, and viruses) have become reinstated as a major public health threat globally. Factors such as antimicrobial resistance and viral complications are the key contributors to the death numbers. As a result, new compounds with structural diversity classes are critical for controlling the virulence of pathogens that are multi-drug resistant. Derivatization of bio-active organic molecules with organometallic synthons is a promising strategy for modifying the inherent and enhanced properties of biomolecules. Due to their redox chemistry, bioactivity, and structural diversity, organometallic moieties make excellent candidates for lead structures in drug development. Furthermore, organometallic compounds open an array of potential in therapy that existing organic molecules lack, i.e., their ability to fulfill drug availability and resolve the frequent succumbing of organic molecules to drug resistance. Additionally, metal complexes have the potential towards metal-specific modes of action, preventing bacteria from developing resistance mechanisms. This review's main contribution is to provide a thorough account of the biological efficacy (in vitro and in vitro) of metal-based complexes against infectious diseases. This resource can also be utilized in conjunction with corresponding journals on metal-based complexes investigated against infectious diseases.

Therapeutic Potential of Marine-Derived Cyclic Peptides as Antiparasitic Agents.

Parasitic diseases still compromise human health. Some of the currently available therapeutic drugs have limitations considering their adverse effects, questionable efficacy, and long treatment, which have encouraged drug resistance. There is an urgent need to find new, safe, effective, and affordable antiparasitic drugs. Marine-derived cyclic peptides have been increasingly screened as candidates for developing new drugs. Therefore, in this review, a systematic analysis of the scientific literature was performed and 25 marine-derived cyclic peptides with antiparasitic activity (1-25) were found. Antimalarial activity is the most reported (51%), followed by antileishmanial (27%) and antitrypanosomal (20%) activities. Some compounds showed promising antiparasitic activity at the nM scale, being active against various parasites. The mechanisms of action and targets for some of the compounds have been investigated, revealing different strategies against parasites.

Acute toxicity of praziquantel to fish Danio rerio and planktonic crustacean Daphnia magna.

This study evaluated the toxicity of the pyrazino isoquinoline anthelmintic praziquantel (PZQ) to the Danio rerio zebrafish and Daphnia magna water flea. The estimated 24 h and 96 h LC50 of PZQ to the zebrafish was 39.9 mg/l and 30.4 mg/l, respectively. The highest 24 h and 96 h non-lethal concentration (LC0) was 21.7 mg/l and 21.2 mg/l, respectively. The mobility inhibition test of the juvenile Daphnia magna revealed a 48 h EC50 of 42.7 mg/l.