Search Results (14)

The emergence and spread of drug-resistant Plasmodium falciparum parasites shed a serious concern on the worldwide control of malaria, the most important tropical disease in terms of mortality and morbidity. This situation has led us to consider the use of peptide-alkoxyamine derivatives as new antiplasmodial prodrugs that could potentially be efficient in the fight against resistant malaria parasites. Indeed, the peptide tag of the prodrug has been designed to be hydrolysed by parasite digestive proteases to afford highly labile alkoxyamines drugs, which spontaneously and instantaneously homolyse into two free radicals, one of which is expected to be active against P. falciparum. Since the parasite enzymes should trigger the production of the active drug in the parasite’s food vacuoles, our approach is summarized as “to dig its grave with its fork”. However, despite promising sub-micromolar IC₅₀ values in the classical chemosensitivity assay, more in-depth tests evidenced that the anti-parasite activity of these compounds could be due to their cytostatic activity rather than a truly anti-parasitic profile, demonstrating that the antiplasmodial activity cannot be based only on measuring antiproliferative activity. It is therefore imperative to distinguish, with appropriate tests, a genuinely parasiticidal activity from a cytostatic activity. Full article

Malaria, Chagas disease, and leishmaniasis are tropical diseases caused by protozoan parasites of the genera Plasmodium, Trypanosoma and Leishmania, respectively. These diseases constitute a major burden on public health in several regions worldwide, mainly affecting low-income populations in economically poor countries. Severe side effects of currently available drug treatments and the emergence of resistant parasites need to be addressed by the development of novel drug candidates. Natural 2,5-Diketopiperazines (2,5-DKPs) constitute N-heterocyclic secondary metabolites with a wide range of biological activities of medicinal interest. Its structural and physicochemical properties make the 2,5-DKP ring a versatile, peptide-like, and stable pharmacophore attractive for synthetic drug design. In the present work, twenty-three novel synthetic 2,5-DKPs, previously synthesized through the versatile Ugi multicomponent reaction, were assayed for their anti-protozoal activities against P. falciparum, T. cruzi, and L. infantum. Some of the 2,5-DKPs have shown promising activities against the target protozoans, with inhibitory concentrations (IC₅₀) ranging from 5.4 to 9.5 µg/mL. The most active compounds also show low cytotoxicity (CC₅₀), affording selectivity indices ≥ 15. Results allowed for observing a clear relationship between the substitution pattern at the aromatic rings of the 2,5-DKPs and their corresponding anti-Plasmodium activity. Finally, calculated drug-like properties of the compounds revealed points for further structure optimization of promising drug candidates. Full article

Ongoing therapy for human parasite infections has a few known drugs but with serious side effects and the problem of drug resistance, impelling us to discover novel drug candidates with newer mechanisms of action. Universally, this has boosted the research in the design and development of novel medicinal agents as antiparasitic drugs with a novel mode of action. Histone deacetylase inhibitors (HDACis) are used in a vast variety of diseases due to their anti-inflammatory properties. Drug repurposing strategies have already approved HDACis as cancer therapeutics and are now under investigation for many parasitic infections. Along with the expression of the gene, histone deacetylase (HDAC) enzymes also act as a slice of great multi-subunit complexes, targeting many non-histones, changing systemic and cellular levels signaling, and producing different cell-based specified effects. Zinc (Zn²⁺)- and nicotinamide adenine dinucleotide (NAD⁺)-dependent HDACs of parasites play pivotal roles in the alteration of gene expression of parasites. Some of them are already known to be responsible for the survival of several parasites under odd circumstances; thus, targeting them for therapeutic interventions will be novel for potential antiparasitic targets. This point of view outlines the knowledge of both class-I and class-II HDACis and sirtuin inhibitors that emerged to be the key players in the treatment of human parasitic disorders like Leishmaniasis, Schistosomiasis, Malaria, Trypanosomiasis, and Toxoplasmosis. This review also focuses on repurposing opportunities and challenges in HDAC inhibitors that are preceded by their clinical development as potent new antiparasitic drugs. Full article

In this study, we introduce semi-supervised machine learning models designed to predict molecular properties. Our model employs a two-stage approach, involving pre-training and fine-tuning. Particularly, our model leverages a substantial amount of labeled and unlabeled data consisting of SMILES strings, a text representation system for molecules. During the pre-training stage, our model capitalizes on the Masked Language Model, which is widely used in natural language processing, for learning molecular chemical space representations. During the fine-tuning stage, our model is trained on a smaller labeled dataset to tackle specific downstream tasks, such as classification or regression. Preliminary results indicate that our model demonstrates comparable performance to state-of-the-art models on the chosen downstream tasks from MoleculeNet. Additionally, to reduce the computational overhead, we propose a new approach taking advantage of 3D compound structures for calculating the attention score used in the end-to-end transformer model to predict anti-malaria drug candidates. The results show that using the proposed attention score, our end-to-end model is able to have comparable performance with pre-trained models. Full article

Leishmaniasis is a group of infectious diseases caused by Leishmania protozoa. The ineffectiveness, high toxicity, and/or parasite resistance of the currently available antileishmanial drugs has created an urgent need for safe and effective leishmaniasis treatment. Currently, the molecular-docking technique is used to predict the proper conformations of small-molecule ligands and the strength of the contact between a protein and a ligand, and the majority of research for the development of new drugs is centered on this type of prediction. Leishmania N-myristoyltransferase (NMT) has been shown to be a reliable therapeutic target for investigating new anti-leishmanial molecules through this kind of virtual screening. Natural products provide an incredible source of affordable chemical scaffolds that serve in the development of effective drugs. Withania somnifera leaves, roots, and fruits have been shown to contain withanolide and other phytomolecules that are efficient anti-protozoal agents against Malaria, Trypanosoma, and Leishmania spp. Through a review of previously reported compounds from W. somnifera-afforded 35 alkaloid, phenolic, and steroid compounds and 132 withanolides/derivatives, typical of the Withania genus. These compounds were subjected to molecular docking screening and molecular dynamics against L. major NMT. Calycopteretin-3-rutinoside and withanoside IX showed the highest affinity and binding stability to L. major NMT, implying that these compounds could be used as antileishmanial drugs and/or as a scaffold for the design of related parasite NMT inhibitors with markedly enhanced binding affinity. Full article

The medicinal plant Artabotrys hexapetalus (synonyms: A.uncinatus and A. odoratissimus) is known as yingzhao in Chinese. Extracts of the plant have long been used in Asian folk medicine to treat various symptoms and diseases, including fevers, microbial infections, ulcers, hepatic disorders and other health problems. In particular, extracts from the roots and fruits of the plant are used for treating malaria. Numerous bioactive natural products have been isolated from the plant, mainly aporphine (artabonatines, artacinatine) and benzylisoquinoline (hexapetalines) alkaloids, terpenoids (artaboterpenoids), flavonoids (artabotrysides), butanolides (uncinine, artapetalins) and a small series of endoperoxides known as yingzhaosu A-to-D. These natural products confer antioxidant, anti-inflammatory and antiproliferative properties to the plant extracts. The lead compound yingzhaosu A displays marked activities against the malaria parasites Plasmodium falciparum and P. berghei. Total syntheses have been developed to access yingzhaosu compounds and analogues, such as the potent compound C14-epi-yingzhaosu A and simpler molecules with a dioxane unit. The mechanism of action of yingzhaosu A points to an iron(II)-induced degradation leading to the formation of two alkylating species, an unsaturated ketone and a cyclohexyl radical, which can then react with vital parasitic proteins. A bioreductive activation of yingzhaosu A endoperoxide can also occur with the heme iron complex. The mechanism of action of yingzhaosu endoperoxides is discussed, to promote further chemical and pharmacological studies of these neglected, but highly interesting bioactive compounds. Yingzhaosu A/C represent useful templates for designing novel antimalarial drugs. Full article

Parasites belonging to the Apicomplexa phylum still represent a major public health and world-wide socioeconomic burden that is greatly amplified by the spread of resistances against known therapeutic drugs. Therefore, it is essential to provide the scientific and medical communities with innovative strategies specifically targeting these organisms. In this review, we present an overview of the diversity of the phosphatome as well as the variety of functions that phosphatases display throughout the Apicomplexan parasites’ life cycles. We also discuss how this diversity could be used for the design of innovative and specific new drugs/therapeutic strategies. Full article

Artemisinin, the most famous anti-malaria drug initially extracted from Artemisia annua L., also exhibits anti-tumor properties in vivo and in vitro. To improve its solubility and bioavailability, multiple derivatives have been synthesized. However, to reveal the anti-tumor mechanism and improve the efficacy of these artemisinin-type drugs, studies have been conducted in recent years. In this review, we first provide an overview of the effect of artemisinin-type drugs on the regulated cell death pathways, which may uncover novel therapeutic approaches. Then, to overcome the shortcomings of artemisinin-type drugs, we summarize the recent advances in two different therapeutic approaches, namely the combination therapy with biologics influencing regulated cell death, and the use of nanocarriers as drug delivery systems. For the former approach, we discuss the superiority of combination treatments compared to monotherapy in tumor cells based on their effects on regulated cell death. For the latter approach, we give a systematic overview of nanocarrier design principles used to deliver artemisinin-type drugs, including inorganic-based nanoparticles, liposomes, micelles, polymer-based nanoparticles, carbon-based nanoparticles, nanostructured lipid carriers and niosomes. Both approaches have yielded promising findings in vitro and in vivo, providing a strong scientific basis for further study and upcoming clinical trials. Full article

Specific adhesion of P. falciparum parasite-infected erythrocytes (IE) in deep vascular beds can result in severe complications, such as cerebral malaria, placental malaria, respiratory distress, and severe anemia. Cerebral malaria and severe malaria syndromes were associated previously with sequestration of IE to a microvasculature receptor ICAM-1. The screening of Torrey Pines Scaffold Ranking library, which consists of more than 30 million compounds designed around 75 molecular scaffolds, identified small molecules that inhibit cytoadhesion of ICAM-1-binding IE to surface-immobilized receptor at IC₅₀ range down to ~350 nM. With their low cytotoxicity toward erythrocytes and human endothelial cells, these molecules might be suitable for development into potentially effective adjunct anti-adhesion drugs to treat cerebral and/or severe malaria syndromes. Our two-step high-throughput screening approach is specifically designed to work with compound mixtures to make screening and deconvolution to single active compounds fast and efficient. Full article

Sulphadoxine and pyrimethamine (SP) have been used as long-acting partner antimalarial drugs in artemisinin combination therapy (ACT) for falciparum malaria. The emergence and increasing spread of SP resistance in malaria-endemic areas have become a challenge for the control of malaria. Therefore, regular monitoring of the mutation status of partner drugs is important for the better management of drug policy. There are limitations with traditional molecular methods and there is an urgent need for an easy method for diagnosis of drug resistance. In this study we have introduced and developed a novel single nucleotide polymorphism loop-mediated isothermal amplification (SNP–LAMP) approach based on a hydroxynaphthol blue (HNB) indicator for the easier and quicker detection of pyrimethamine resistance in Plasmodium falciparum malaria. To implement this novel approach, many sets of LAMP primers were designed and tested. Finally, one set of forward inner primer M1 (FIPM1) of LAMP primer was selected that specifically distinguishes pyrimethamine-resistant P. falciparum malaria. The LAMP reactions were optimized at 60–66 °C for 45 min. High sensitivity (7 parasites/µL) was observed with 10⁻⁴ fold dilutions (<2 ng DNA) of genomic DNA. Moreover, this approach has the potential to be applied even in laboratories unfamiliar with PCR or other molecular methods, and in future, this can be helpful for the better management of anti-malarial policy. Full article

Dinitroanilines are chemical compounds with high selectivity for plant cell α-tubulin in which they promote microtubule depolymerization. They target α-tubulin regions that have diverged over evolution and show no effect on non-photosynthetic eukaryotes. Hence, they have been used as herbicides over decades. Interestingly, dinitroanilines proved active on microtubules of eukaryotes deriving from photosynthetic ancestors such as Toxoplasma gondii and Plasmodium falciparum, which are responsible for toxoplasmosis and malaria, respectively. By combining differential in silico screening of virtual chemical libraries on Arabidopsis thaliana and mammal tubulin structural models together with cell-based screening of chemical libraries, we have identified dinitroaniline related and non-related compounds. They inhibit plant, but not mammalian tubulin assembly in vitro, and accordingly arrest A. thaliana development. In addition, these compounds exhibit a moderate cytotoxic activity towards T. gondii and P. falciparum. These results highlight the potential of novel herbicidal scaffolds in the design of urgently needed anti-parasitic drugs. Full article

Liquid-liquid extraction (LLE) is an established unit operation in the manufacturing process of many products. However, development and integration of multistage LLE for new products and separation routes is often hindered and is probably more cost intensive due to a lack of robust development strategies and reliable process models. Even today, extraction columns are designed based on pilot plant experiments. For dimensioning, knowledge of phase equilibrium, hydrodynamics and mass transport kinetics are necessary. Usually, those must be determined experimentally for scale-up, at least in scales of DN50-150 (nominal diameter). This experiment-based methodology is time consuming and it requires large amounts of feedstock, especially in the early phase of the project. In this study the development for the integration of LLE in a new manufacturing process for artemisinin as an anti-malaria drug is presented. For this, a combination of miniaturized laboratory and mini-plant experiments supported by mathematical modelling is used. System data on extraction and washing distributions were determined by means of shaking tests and implemented as a multi-stage extraction in a process model. After the determination of model parameters for mass transfer and plant hydrodynamics in a droplet measurement apparatus, a distributed plug-flow model is used for scale-up studies. Operating points are validated in a mini-plant system. The mini-plant runs are executed in a Kühni-column (DN26) for extraction and a packed extraction column (DN26) for the separation of side components with a throughput of up to 3.6 L/h, yield of up to 100%, and purity of 41% in the feed mixture to 91% after washing. Full article

The article summarizes a systematic process design for the extraction and purification of artemisinin from annual mugwort (Artemisia annua L.). Artemisinin serves as an anti-malaria drug, therefore, resource-efficient and economic processes for its production are needed. The process design was based on lab-scale experiments and afterwards piloted on miniplant-scale at the institute. In this part of the article, a detailed economic feasibility studies including a reference process as a benchmark the lab-scale process and the pilot-scale process is given. Relevant differences between the different scales are discussed. The details of the respective unit operations (solid-liquid extraction, liquid-liquid extraction, chromatography and crystallization) are presented in dedicated articles. The study showed that even miniaturized lab-scale experiments are able to deliver data detailed enough for scale-up calculations on a theoretical basis. To our knowledge, a comparable systematic process design and piloting was never performed by academia before. Full article

According to the World Health Organization, half of the World’s population, approximately 3.3 billion people, is at risk for developing malaria. Nearly 700,000 deaths each year are associated with the disease. Control of the disease in humans still relies on chemotherapy. Drug resistance is a limiting factor, and the search for new drugs is important. We have designed and synthesized new 2-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimidine derivatives based on bioisosteric replacement of functional groups on the anti-malarial compounds mefloquine and amodiaquine. This approach enabled us to investigate the impact of: (i) ring bioisosteric replacement; (ii) a CF₃ group substituted at the 2-position of the [1,2,4]triazolo[1,5-a]pyrimidine scaffold and (iii) a range of amines as substituents at the 7-position of the of heterocyclic ring; on in vitro activity against Plasmodium falciparum. According to docking simulations, the synthesized compounds are able to interact with P. falciparum dihydroorotate dehydrogenase (PfDHODH) through strong hydrogen bonds. The presence of a trifluoromethyl group at the 2-position of the [1,2,4]triazolo[1,5-a]pyrimidine ring led to increased drug activity. Thirteen compounds were found to be active, with IC₅₀ values ranging from 0.023 to 20 µM in the anti-HRP2 and hypoxanthine assays. The selectivity index (SI) of the most active derivatives 5, 8, 11 and 16 was found to vary from 1,003 to 18,478. Full article