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92 Publications visible to you, out of a total of 92
3'-deoxytubercidin: A potent therapeutic candidate for the treatment of Surra and Dourine.

Abstract (Expand)

Surra and Dourine are widespread diseases caused by two protozoan parasites Trypanosoma brucei evansi and Trypanosoma brucei equiperdum, respectively. A wide range of animals including camels, horses, … cattle and buffaloes are susceptible to infection. These diseases pose a significant socio-economic burden, primarily due to the limited therapeutic options and the complications associated with toxicity and drug resistance, making disease management particularly challenging. This study evaluated the potential of 3'-deoxytubercidin, a previously identified antitrypanosomal nucleoside, as a therapeutic candidate for Surra and Dourine using mouse models. Mice infected with either T. b. evansi or T. b. equiperdum were treated with 3'-deoxytubercidin at a dosage of 6.25 mg kg(-1) administrated intraperitoneally once daily for five consecutive days. The treatment resulted in full cure, as confirmed by both microscopic examination and quantitative PCR, without any observed toxicity. Given the importance of considering the One Health concept in developing new antiparasitic drugs for veterinary use, the environmental impact of 3'-deoxytubercidin was assessed through the ecotoxicity tests on aquatic organisms, conducted in accordance with OECD guidelines. The compound showed some toxicity to Daphnia (EC(50) = 0.54 mg L(-1) in acute Daphnia test) but had no significant adverse effects on green alga at concentrations tested (up to 50 mg L(-1)). This study confirms the suitability of 3'-deoxytubercidin as an effective and safe therapeutic candidate for further development in the treatment of Surra and Dourine, highlighting its potential for improving disease management in affected regions.

Authors: K. Ilbeigi, D. Mabille, R. Roy, M. Bundschuh, E. Van de Velde, F. Hulpia, S. Van Calenbergh, G. Caljon

Date Published: 12th Apr 2025

Publication Type: Journal Article

Pyrazolyl amide-chalcones conjugates: Synthesis and antikinetoplastid activity.

Abstract (Expand)

A series of novel pyrazolyl amide-chalcones conjugates was synthesized in five steps and evaluated against a range of medically important kinetoplastid parasites including Trypanosoma cruzi, Trypanosoma … brucei brucei, Trypanosoma brucei rhodesiense and Leishmania infantum. In addition, the series was also tested for in vitro cytotoxicity activity against human lung fibroblasts and primary mouse macrophages. Among all synthetised compounds, 9b was found to be the most active against T. b. brucei with an IC(50) value of 0.51 +/- 0.06 muM. Against T. b. rhodesiense, 9n was found to be the most potent with an IC(50) value of 0.46 +/- 0.07 muM. While against L. infantum, 9a was found to be most active with an IC(50) value of 7.16 +/- 1.88 muM. Based on the results and SAR, further modifications will be carried out to increase potency.

Authors: D. S. Agarwal, R. M. Beteck, D. Mabille, G. Caljon, L. J. Legoabe

Date Published: 9th Apr 2025

Publication Type: Journal Article

Bridging the gap between research and decision making: A European survey to enhance cooperation in wastewater-based epidemiology (WBE) for illicit drugs

Abstract

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Authors: Jose Antonio Baz-Lomba, AlexanderL.N. van Nuijs, Anna Lenart-Boroń, Anna Péterfi, Anne de l’Eprevier, Arndís Sue Ching Löve, Barbara Kasprzyk-Hordern, Christoph Ort, Elisabetta Simeoni, Ester Heath, Evelina Pridotkiene, Foon Yin Lai, Frederic Béen, Herbert Oberacher, Igor Bodík, Iva Valenčić, Jaroslav Slobodnik, Joakim Strandberg, Kevin Sheeran, Laura Alexandra Smit-Rigter, Leon P. Barron, Lubertus Bijlsma, Magda Psichoudaki, Maria Savvidou, Marit Edland-Gryt, Martin Busch, Mateja Jandl, Michael G. Bertram, Miren López de Alda, Nadine Berndt, Nebile Daglioglu, Nikolaos Thomaidis, Loïc Fabien, Pavla Chomynova, Reinhard Oertel, Sara Castiglioni, Selda Mercan, Serap Annette Akgür, Serge Schneider, Teemu Gunnar, Thomas L. ter Laak, Thomas Thiebault, João Pedro Matias

Date Published: 1st Apr 2025

Publication Type: Journal Article

Allosteric inhibition of trypanosomatid pyruvate kinases by a camelid single-domain antibody.

Abstract (Expand)

African trypanosomes are the causative agents of neglected tropical diseases affecting both humans and livestock. Disease control is highly challenging due to an increasing number of drug treatment … failures. African trypanosomes are extracellular, blood-borne parasites that mainly rely on glycolysis for their energy metabolism within the mammalian host. Trypanosomal glycolytic enzymes are therefore of interest for the development of trypanocidal drugs. Here, we report the serendipitous discovery of a camelid single-domain antibody (sdAb aka Nanobody) that selectively inhibits the enzymatic activity of trypanosomatid (but not host) pyruvate kinases through an allosteric mechanism. By combining enzyme kinetics, biophysics, structural biology, and transgenic parasite survival assays, we provide a proof-of-principle that the sdAb-mediated enzyme inhibition negatively impacts parasite fitness and growth.

Authors: J. E. Pinto Torres, M. Claes, R. Hendrickx, M. Yuan, N. Smiejkowska, P. Van Wielendaele, A. Hacisuleyman, H. De Winter, S. Muyldermans, P. A. M. Michels, M. D. Walkinshaw, W. Versees, G. Caljon, S. Magez, Y. G. Sterckx

Date Published: 31st Mar 2025

Publication Type: Journal Article

Reactions of Plasmodium falciparum Type II NADH: Ubiquinone Oxidoreductase with Nonphysiological Quinoidal and Nitroaromatic Oxidants

Abstract (Expand)

In order to detail the antiplasmodial effects of quinones (Q) and nitroaromatic compounds (ArNO2), we investigated their reduction mechanism by Plasmodium falciparum flavoenzyme type II NADH:ubiquinone … oxidoreductase (PfNDH2). The reactivity of Q and ArNO2 (n = 29) follows a common trend and exhibits a parabolic dependence on their single-electron reduction potential (E71), albeit with significantly scattered data. The reactivity of quinones with similar E71 values increases with their lipophilicity. Quinones are reduced by PfNDH2 in a two-electron way, but ArNO2 are reduced in a single-electron way. The inhibition studies using NAD+ and ADP-ribose showed that quinones oxidize the complexes of reduced enzyme with NADH and NAD+. This suggests that, as in the case of other NDH2s, quinones and the nicotinamide ring of NAD(H) bind at separate sites. A scheme of PfNDH2 catalysis is proposed, consistent with both the observed ‘ping-pong’ mechanism and the presence of two substrate binding sites. Molecular docking showed that Q and ArNO2 bind in a similar manner and that lipophilic quinones have a higher affinity for the binding site. One may expect that PfNDH2 can be partially responsible for the previously observed enhanced antiplasmodial activity of aziridinylbenzoquinones caused by their two-electron reduction, as well as for the redox cycling and oxidative stress-type action of ArNO2.

Authors: Lina Misevičienė, Marie-Pierre Golinelli-Cohen, Visvaldas Kairys, Audronė Marozienė, Mindaugas Lesanavičius, Narimantas Čėnas

Date Published: 11th Mar 2025

Publication Type: Journal Article

Nanostructured Lipid Carrier for Intracellular Delivery of a Bis(pyridine-2-carboxamidine) DNA Minor Groove Binder Active against <i>Leishmania</i>

Abstract

Not specified

Authors: J. Jonathan Nué-Martinez, Marta Leo-Barriga, Fernando Herranz, Zisis Koutsogiannis, Paul W. Denny, Godwin U. Ebiloma, Christophe Dardonville, Ana González-Paredes

Date Published: 19th Feb 2025

Publication Type: Journal Article

Flavonolignans silybin, silychristin and 2,3-dehydrosilybin showed differential cytoprotective, antioxidant and anti-apoptotic effects on splenocytes from Balb/c mice

Abstract

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Authors: Zuzana Jurčacková, Gabriela Hrčková, Dagmar Mudroňová, Anna Alexovič Matiašová, David Biedermann

Date Published: 15th Feb 2025

Publication Type: Journal Article

Synthesis of 1,2,3‐Triazole‐Methyl‐Menadione Derivatives: Evaluation of Electrochemical and Antiparasitic Properties against two Blood‐Dwelling Parasites

Abstract (Expand)

AbstractThis study explores the synthesis and evaluation of novel 1,2,3‐triazole‐methyl‐1,4‐naphthoquinone hybrids, focusing on their electrochemical properties and antiparasitic efficacies against two … human blood‐dwelling parasites Plasmodium falciparum and Schistosoma mansoni. Using copper‐catalyzed azide‐alkyne cycloaddition (CuAAC), a well‐established tool in click chemistry, two synthetic routes were assessed to develop α‐ and β‐[triazole‐methyl]‐menadione derivatives. By optimizing the CuAAC reaction conditions, yields were significantly improved, reaching up to 94 % for key intermediates and resulting in the formation of a library of approximately 30 compounds. Biological evaluation of the compounds in antiparasitic drug assays demonstrated notable antischistosomal potencies, while no significant activity was observed for the same series against P. falciparum parasites. Electrochemical and ‘benzylic’ oxidation studies confirmed that the active ‘benzoyl’ metabolite responsible for the antiplasmodial activity of plasmodione cannot be generated. These findings highlight the potential of triazole‐linked menadione hybrids as promising early candidates for antischistosomal drug development, and provides insights into structure‐activity relationships crucial for future therapeutic strategies.

Authors: Baptiste Dupouy, Tanja Karpstein, Cécile Häberli, Monica Cal, Matthias Rottmann, Pascal Mäser, Jennifer Keiser, Mourad Elhabiri, Elisabeth Davioud‐Charvet

Date Published: 8th Jan 2025

Publication Type: Journal Article

New <i>Trypanosoma brucei</i> acting derivatives incorporating 1-(4-phenyl)adamantane and 1-(4-phenoxyphenyl)adamantane

Abstract (Expand)

New 1-(4-phenyl)adamantane and 1-(4-phenoxyphenyl)adamantane derivatives, functionalised with imidazolines, linear amidines, aminoguanylhydrazone and thiosemicarbazone moieties present activity against … T. brucei .

Authors: Konstantina Stavropoulou, Angeliki Kaimaki, Maria Nikolaou, Ana K. Brown, Andrew Tsotinis, Martin C. Taylor, John M. Kelly, Ioannis P. Papanastasiou

Date Published: 2025

Publication Type: Journal Article

Development of environmentally biodegradable drugs: what are the key challenges?

Abstract

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Authors: Michael G. Bertram, Bob B.M. Wong, Klaus Kümmerer, Manuela Jörg

Date Published: 24th Dec 2024

Publication Type: Journal Article

Click Coupling of Flavylium Dyes with Plasmodione Analogues: Towards New Redox‐Sensitive Pro‐Fluorophores

Abstract (Expand)

Abstract The development of redox‐sensitive molecular fluorescent probes for the detection of redox changes in Plasmodium falciparum ‐parasitized red blood cells remains of interest due to the limitations … ‐parasitized red blood cells remains of interest due to the limitations of current genetically encoded biosensors. This study describes the design, screening and synthesis of new pro‐fluorophores based on flavylium azido dyes coupled by CuAAC click chemistry to alkynyl analogues of plasmodione oxide, the key metabolite of the potent redox‐active antimalarial plasmodione. The photophysical and electrochemical properties of these probes were evaluated, focusing on their fluorogenic responses. The influence of both the redox status of the quinone and the length of the PEG chain separating the fluorophore from the electrophore on the photophysical properties was investigated. The fluorescence quenching by photoinduced electron transfer is reversible and of high amplitude for probes in oxidized quinone forms and fluorescence is reinstated for reduced hydroquinone forms. Our results demonstrate that shortening the PEG chain has the effect of enhancing the fluorogenic response, likely due to non‐covalent interactions between the two chromophores. All these systems were evaluated for their antiparasitic activities and fluorescence imaging suggests the efficacy of the fluorescent flavylium dyes in P. falciparum ‐parasitized red blood cells, paving the way for future parasite imaging studies to monitor cellular redox processes.

Authors: Baptiste Dupouy, Leandro Cotos, Annika Binder, Lucie Slavikova, Matthias Rottmann, Pascal Mäser, Denis Jacquemin, Markus Ganter, Elisabeth Davioud‐Charvet, Mourad Elhabiri

Date Published: 16th Dec 2024

Publication Type: Journal Article

Discovery and Development of an Advanced Lead for the Treatment of African Trypanosomiasis

Abstract

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Authors: Kayhan Ilbeigi, Dorien Mabille, An Matheeussen, Rik Hendrickx, Mathieu Claes, Nick Van Reet, Roel Anthonissen, Fabian Hulpia, Cai Lin, Louis Maes, Clement Regnault, Phillip Whitfield, Rajdeep Roy, Marzuq A. Ungogo, Yann G.-J. Sterckx, Hans De Winter, Birgit Mertens, Mirco Bundschuh, Harry P. De Koning, Serge Van Calenbergh, Guy Caljon

Date Published: 12th Dec 2024

Publication Type: Journal Article

Biological properties and in silico studies of thiazolopyrimidine derivatives active against visceral and cutaneous Leishmania spp. amastigote forms

Abstract

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Authors: Gulsah Bayraktar, Pascal Marchand, Euzébio Guimarães Barbosa, Marilia Cecilia da Silva, Karen Cacilda Weber, Sandrine Cojean, Merve Saylam, Huseyin Istanbullu

Date Published: 1st Dec 2024

Publication Type: Journal Article

Regioselective Synthesis of Potential Non-Quinonoid Prodrugs of Plasmodione: Antiparasitic Properties Against Two Hemoglobin-Feeding Parasites and Drug Metabolism Studies

Abstract (Expand)

Ψ-1,4-naphthoquinones (Ψ-NQ) are non-quinoid compounds in which aromaticity—found in 1,4-naphthoquinones—is broken by the introduction of an angular methyl at C-4a or -8a. This series was designed to … act as prodrugs of 1,4-naphthoquinones in an oxidative environment. Furthermore, from a medicinal chemistry point of view, the loss of planarity of the scaffold might lead to an improved solubility and circumvent the bad reputation of quinones in the pharmaceutical industry. In this work, we illustrated the concept by the synthesis of Ψ -plasmodione regioisomers as prodrugs of the antimalarial plasmodione. The presence of a chiral center introduces a new degree of freedom to be controlled by enantioselectivity and regioselectivity of the cycloaddition in the Diels–Alder reaction. The first strategy that was followed was based on the use of a chiral enantiopure sulfoxide to govern the stereoselective formation of (+)Ψ-NQ or (−)Ψ-NQ, depending on the chirality of the sulfoxide (R or S). New sulfinylquinones were synthesized but were found to be ineffective in undergoing cycloaddition with different dienes under a wide range of conditions (thermal, Lewis acid). The second strategy was based on the use of boronic acid-substituted benzoquinones as auxiliaries to control the regioselectivity. Using this methodology to prepare the (±)Ψ-NQ racemates, promising results (very fast cycloaddition time: ~2 h) were obtained with boronic acid-based quinones 25 and 27 in the presence of 1-methoxy-1,3-butadiene, to generate the 4a- and the 8a-Ψ-plasmodione regioisomers 1 and 2 (synthesized in six steps with a total yield of 10.5% and 4.1%, respectively. As the expected prodrug effect can only be revealed if the molecule undergoes an oxidation of the angular methyl, e.g., in blood-feeding parasites that digest hemoglobin from the host, the antimalarial and the antischistosomal properties of both (±)Ψ-NQ regioisomers were determined in drug assays with Plasmodium falciparum and Schistosoma mansoni. Metabolic studies under quasi-physiological conditions and LC-MS analyses were undertaken to reveal the generation of plasmodione from both the 4a- and the 8a-Ψ-plasmodione regioisomers.

Authors: Elena Cesar-Rodo, Baptiste Dupouy, Cécile Häberli, Jean-Marc Strub, David L. Williams, Pascal Mäser, Matthias Rottmann, Jennifer Keiser, Don Antoine Lanfranchi, Elisabeth Davioud-Charvet

Date Published: 7th Nov 2024

Publication Type: Journal Article

Environmental impacts of drugs against parasitic vector-borne diseases and the need to integrate sustainability into their development and use

Abstract (Expand)

<ns3:p> Background The current scientific discourse on environmental impacts of veterinary medicines mostly focuses on ectoparasiticides. Meanwhile, the environmental impacts of widely prescribed …of widely prescribed drugs for the treatment of human and animal parasitic vector-borne diseases (PVBD) remain largely unexplored. There is thus a need for evidence-based information to support guidelines and protocols for sustainable One Health PVBD drug development and use, while promoting greener research practices. Here, we reflect on the potential environmental impacts of PVBD drugs in current use, and the environmental impact of our research practices for developing new antiparasitics. Methods We conducted a survey of the membership of the “One Health drugs against parasitic vector borne diseases in Europe and beyond” Cooperation in Science and Technology (COST) Action 21111 (OneHealth <ns3:italic>drugs</ns3:italic> ) to assess the current appreciation of sustainable drug design concepts and the extent to which One Health and sustainability principles are integrated into PVBD drug discovery and development. The survey also explored which human, technical, and funding resources are currently used in Europe and neighbouring countries in PVBD drugs research. Results The survey was conducted and analysed by OneHealth <ns3:italic>drugs</ns3:italic> and garnered 89 respondents, representing a response rate of 66% from 32 countries, predominantly European. 87% of participating collaborators worked in Academia; research groups were small (60% with 1–4 researchers) and mostly consist of few researchers, mostly at early career stages (63% <35 years old). Collaborations were mostly between academics, and 60% collaborated with non-European researchers, while funding was mostly from national governments. Motivation for greener research practices was high but there was as yet low implementation of green strategies or the incorporation of ecotoxicological test in drug development workflows, due to cost and unfamiliarity. Conclusions We highlight the need for early-ecotoxicological testing of new drug candidates and suggest best practices as we move towards standardized protocols in developing safe and efficacious PVBD drugs. </ns3:p>

Authors: Clara M. Lima, Elisa Uliassi, Eli S.J. Thoré, Michael G. Bertram, Luis Cardoso, Anabela Cordeiro da Silva, Maria Paola Costi, Harry P. de Koning

Date Published: 4th Nov 2024

Publication Type: Journal Article

Hydrazinated geraniol derivatives as potential broad-spectrum antiprotozoal agents.

Abstract (Expand)

Geraniol, a primary component of several essential oils, has been associated with broad-spectrum antiprotozoal activities, although moderate to weak. This study primarily concentrated on the synthesis … of hydrazinated geraniol derivatives as potential antiprotozoal agents. The synthesised compounds were tested in vitro against different parasitic protozoans of clinical relevance, including Trypanosoma brucei brucei, Trypanosoma brucei rhodesiense, Trypanosoma cruzi and Leishmania infantum. Compounds 6, 8, 13, 14 and 15 demonstrated low micromolar activity against the different parasites. Compounds 8, 13, 14 and 15 had the highest efficacy against Trypanosoma brucei rhodesiense, as indicated by their respective IC(50) values of 0.74, 0.56, 1.26 and 1.00 microM. Compounds 6, 14 and 15 displayed the best activity against Trypanosoma brucei brucei, with IC(50) values of 1.49, 1.48 and 1.85 microM, respectively. The activity of compounds 6, 14 and 15 also extended to intracellular Trypanosoma cruzi, with IC(50) values of 5.14, 6.30 and 4.90 microM, respectively. Compound 6, with an IC(50) value of 11.73 microM, and compound 14, with an IC(50) value of 8.14 microM, demonstrated some modest antileishmanial activity.

Authors: J. Jooste, L. J. Legoabe, K. Ilbeigi, G. Caljon, R. M. Beteck

Date Published: 4th Oct 2024

Publication Type: Journal Article

3-Benzylmenadiones and their Heteroaromatic Analogues Target the Apicoplast of Apicomplexa Parasites: Synthesis and Bioimaging Studies

Abstract

Not specified

Authors: Baptiste Dupouy, Maxime Donzel, Matthieu Roignant, Sarah Charital, Rodrigue Keumoe, Yoshiki Yamaryo-Botté, Alexander Feckler, Mirco Bundschuh, Yann Bordat, Matthias Rottmann, Pascal Mäser, Cyrille Y. Botté, Stéphanie A. Blandin, Sébastien Besteiro, Elisabeth Davioud-Charvet

Date Published: 27th Sep 2024

Publication Type: Journal Article

Effect of Leishmania infantum infection on B cell lymphopoiesis and memory in the bone marrow and spleen.

Abstract (Expand)

Visceral leishmaniasis (VL) is characterized by an uncontrolled infection of internal organs such as the spleen, liver and bone marrow (BM) and can be lethal when left untreated. No effective vaccination … is currently available for humans. The importance of B cells in infection and VL protective immunity has been controversial, with both detrimental and protective effects described. VL infection was found in this study to increase not only all analyzed B cell subsets in the spleen but also the B cell progenitors in the BM. The enhanced B lymphopoiesis aligns with the clinical manifestation of polyclonal hypergammaglobulinemia and the occurrence of autoantibodies. In line with earlier reports, flow cytometric and microscopic examination identified parasite attachment to B cells of the BM and spleen without internalization, and transformation of promastigotes into amastigote morphotypes. The interaction appears independent of IgM expression and is associated with an increased detection of activated lysosomes. Furthermore, the extracellularly attached amastigotes could be efficiently transferred to infect macrophages. The observed interaction underscores the potentially crucial role of B cells during VL infection. Additionally, using immunization against a fluorescent heterologous antigen, it was shown that the infection does not impair immune memory, which is reassuring for vaccination campaigns in VL endemic areas.

Authors: L. Dirkx, M. Loyens, S. I. Van Acker, D. Bulte, M. Claes, M. Radwanska, S. Magez, G. Caljon

Date Published: 31st Aug 2024

Publication Type: Journal Article

Veterinary perspectives on the urbanization of leishmaniosis in Morocco

Abstract (Expand)

Abstract Background Leishmaniosis caused by Leishmania infantum, L. major and L. tropica is endemic in Morocco. Growing evidence of both human and canine Leishmania infections in urban centres has been …ctions in urban centres has been reported. Since many forms of the disease are zoonotic, veterinarians play an important role in leishmaniosis control by intervening at the parasite host level. This study aimed to bring together One Health principles to connect canine and feline leishmaniosis epidemiology within urban centres of Morocco (Rabat and Fez) and assess the level of awareness of Moroccan veterinarians about facing this threat. Methods A molecular survey was conducted for Leishmania DNA detection in canine (n = 155) and feline (n = 32) whole-blood samples. Three conventional polymerase chain reaction (PCR) protocols were implemented. The first PCR aimed at identifying infected animals by targeting Leishmania spp. kinetoplast minicircle DNA (kDNA). The second and third PCR targeted the Leishmania internal transcribed spacer region (ITS-1) and the Leishmania small subunit ribosomal RNA (SSUrRNA) gene, respectively, aiming at identification of the infecting species after Sanger sequencing-positive amplicons. Total immunoglobulin G (IgG) against Leishmania spp. was evaluated in 125 dogs by enzyme-linked immunosorbent assays (ELISA) using an in-house protocol, including three Leishmania-specific antigens (SPLA, rKDDR and LicTXNPx). Sera from 25 cats were screened for total IgG to Leishmania spp. by an indirect immunofluorescence antibody test (IFAT). An online questionnaire was presented to Moroccan veterinarians addressing their knowledge and practices towards animal leishmaniosis. Results Overall, 19.4% of the dogs tested positive for Leishmania kDNA and ITS-1 and sequencing revealed infection with L. infantum among PCR-positive dogs. These animals presented a wide range of ELISA seropositivity results (16.7%, 34.9% and 51.6%) according to the tested antigens (rKDDR, SPLA and LicTXNPx, respectively). Use of kDNA-PCR revealed 12.5% cats positive to Leishmania spp. otherwise found to be seronegative by IFAT. Conclusions A considerable prevalence of infection was identified in dogs from urban centres of Morocco. Additionally, this is the first report of feline infection with Leishmania spp. in this country and in urban settings. Moroccan veterinarians are aware that animal leishmaniosis is endemic in Morocco, representing a public health threat, and are knowledgeable about canine leishmaniosis diagnosis and treatment. Graphical Abstract

Authors: Clara M. Lima, Maria Bourquia, Abderrahmane Zahri, Nada Haissen, Nuno Santarém, Luís Cardoso, Anabela Cordeiro da Silva

Date Published: 19th Aug 2024

Publication Type: Journal Article

A breath of fresh air: impact of insect-borne protozoan parasites on the respiratory system.

Abstract (Expand)

The protozoan parasites Plasmodium, Leishmania, and Trypanosoma are transmitted by hematophagous insects and cause severe diseases in humans. These infections pose a global threat, particularly in … low-resource settings, and are increasingly extending beyond the current endemic regions. Tropism of parasites is crucial for their development, and recent studies have revealed colonization of noncanonical tissues, aiding their survival and immune evasion. Despite receiving limited attention, cumulative evidence discloses the respiratory system as a significant interface for host-pathogen interactions, influencing the course of (co)infection and disease onset. Due to its pathophysiological and clinical implications, we emphasize that further research is needed to better understand the involvement of the respiratory system and its potential to improve prevention, diagnosis, treatment, and interruption of the chain of transmission.

Authors: S. Araujo, D. Mabille, A. B. Garcia, G. Caljon

Date Published: 9th Aug 2024

Publication Type: Journal Article

N-Pyrazolyl- and N-Triazolylamines and -Ureas as Antileishmanial and Antitrypanosomal Drugs.

Abstract (Expand)

Three types of modifications of antileishmanial pyrazole lead compounds 7 and 8 were conducted to expand understanding of the relationships between structural features and antileishmanial/antitrypanosomal … activity: (1) the pyrazole core was retained or replaced by a 1,2,4-triazole ring; (2) various aryl moieties including 2-fluorophenyl, pyridin-3-yl and pyrazin-2-yl rings were attached at 3-position of the core azole; (3) either arylmethylamino or ureido substituents were introduced at 5-position of the azole core. The synthesis followed established routes starting with esters 9 or 15 and anhydride 21. The synthesized 3-arylpyrazoles and 3-aryl-1,2,4-triazoles had only very low antileishmanial activity. The 2-fluorophenyl-substituted pyrazole 18c revealed the highest antileishmanial activity of this series of compounds, but its IC(50) value (20 muM) still indicates low activity. However, low micromolar antitrypanosomal activity was detected for the pyridin-3-yl-substituted pyrazoles 12b (IC(50)=4.7 muM) and 14a (IC(50)=2.1 muM). Their IC(50) values are comparable with the IC(50) values of the reference compounds benznidazole and nifurtimox. Whereas only low unspecific cytotoxicity at the primary peritoneal mouse macrophages (PMM) was detected, considerable cytotoxicity at MRC-5 human fibroblast cells was found for both pyrazoles 12b an 14a. The activity of pyrazole 12b against T. cruzi is 4-fold higher than its unspecific MRC-5 cytotoxicity.

Authors: T. Winge, L. Imberg, B. Perry, A. Matheeussen, G. Caljon, D. Kalinin, B. Wunsch

Date Published: 1st Aug 2024

Publication Type: Journal Article

The activities of suaveolol and other compounds from Hyptis suaveolens and Momordica charantia against the aetiological agents of African trypanosomiasis, leishmaniasis and malaria

Abstract

Not specified

Authors: Enimie E. Oaikhena, Umar A. Yahaya, Sani M. Abdulsalami, Nkechi L. Egbe, Modupe M. Adeyemi, Marzuq A. Ungogo, Godwin U. Ebiloma, Felix K. Zoiku, Prince A. Fordjour, Hamza A.A. Elati, Neils B. Quashie, John O. Igoli, Alexander I. Gray, Christopher Lawson, Valerie A. Ferro, Harry P. de Koning

Date Published: 1st Aug 2024

Publication Type: Journal Article

Spliced-Leader RNA as a Dynamic Marker for Monitoring Viable Leishmania Parasites During and After Treatment.

Abstract (Expand)

Accurate detection of viable Leishmania parasites is critical for evaluating visceral leishmaniasis (VL) treatment response at an early timepoint. We compared the decay of kinetoplast DNA (kDNA) and … spliced-leader RNA (SL-RNA) in vitro, in vivo, and in a VL patient cohort. An optimized combination of blood preservation and nucleic acid extraction improved efficiency for both targets. SL-RNA degraded more rapidly during treatment than kDNA, and correlated better with microscopic examination. SL-RNA quantitative polymerase chain reaction emerges as a superior method for dynamic monitoring of viable Leishmania parasites. It enables individualized treatment monitoring for improved prognoses and has potential as an early surrogate endpoint in clinical trials.

Authors: R. Hendrickx, R. Melkamu, D. Tadesse, T. Teferi, P. B. Feijens, M. Vleminckx, S. van Henten, F. Alves, T. Shibru, J. van Griensven, G. Caljon, M. Pareyn

Date Published: 25th Jul 2024

Publication Type: Journal Article

Metronidazole Interaction with Cu(2+) and Zn(2+): Speciation Study in Aqueous Solution and Biological Activity Evaluation.

Abstract (Expand)

Metronidazole (2-methyl-5-nitro-1H-imidazole-1-ethanol, MNZ) is a well-known and widely used drug for its excellent activity against various anaerobic bacteria and protozoa. The purpose of this study … is to elucidate the ability of MNZ to form metal complexes with Cu(2+) and Zn(2+) and to demonstrate that complexation increases its bioactivity profile against different pathogenic microorganisms. The interaction of MNZ with Cu(2+) and Zn(2+) was investigated in NaCl aqueous solution under different conditions of temperature (15, 25, and 37 degrees C) and ionic strength (0.15, 0.5, and 1 mol L(-1)) by potentiometric and spectrophotometric titrations. The obtained speciation models include two species for the Cu(2+)-containing system, namely, CuL and CuL(2), and three species for the Zn(2+)-containing system, namely, ZnLH, ZnL, and ZnLOH. The formation constants of the species were calculated and their dependence on temperature and ionic strength evaluated. Comparison of the sequestering ability of MNZ under physiological conditions revealed a capacity toward Cu(2+) higher than that toward Zn(2+). A simulation under the same conditions also showed a significant percentage of the Cu(2+)-MNZ species. The biological assessments highlighted that the complexation of MNZ with Cu(2+) has a relevant impact on the potency of the drug against two Trypanosoma spp. (i.e., T. b. brucei and T. b. rhodesiense) and one gram-(-) bacterial species (i.e., Escherichia coli). It is noteworthy that the increased potency upon complexation with Cu(2+) did not result in cytotoxicity against MRC-5 human fetal lung fibroblasts and primary peritoneal mouse macrophages.

Authors: F. Carnamucio, C. Foti, N. Micale, N. Van Pelt, A. Matheeussen, G. Caljon, O. Giuffre

Date Published: 2nd Jul 2024

Publication Type: Journal Article

Identification of Innovative Folate Inhibitors Leveraging the Amino Dihydrotriazine Motif from Cycloguanil for Their Potential as Anti-<i>Trypanosoma brucei</i> Agents

Abstract

Not specified

Authors: Valeria Francesconi, Marco Rizzo, Cecilia Pozzi, Lorenzo Tagliazucchi, Claude U. Konchie Simo, Giulia Saporito, Giacomo Landi, Stefano Mangani, Anna Carbone, Silvia Schenone, Nuno Santarém, Joana Tavares, Anabela Cordeiro-da-Silva, Maria Paola Costi, Michele Tonelli

Date Published: 2nd Jul 2024

Publication Type: Journal Article

In Vivo Bioluminescence Imaging Reveals Differences in Leishmania infantum Parasite Killing Kinetics by Antileishmanial Reference Drugs.

Abstract (Expand)

The bioluminescent Leishmania infantum BALB/c mouse model was used to evaluate the parasiticidal drug action kinetics of the reference drugs miltefosine, paromomycin, sodium stibogluconate, and liposomal … amphotericin B. Infected mice were treated for 5 days starting from 7 days post-infection, and parasite burdens were monitored over time via bioluminescence imaging (BLI). Using nonlinear regression analyses of the BLI signal, the parasite elimination half-life (t(1/2)) in the liver, bone marrow, and whole body was determined and compared for the different treatment regimens. Significant differences in parasiticidal kinetics were recorded. A single intravenous dose of 0.5 mg/kg liposomal amphotericin B was the fastest acting with a t(1/2) of less than 1 day. Intraperitoneal injection of paromomycin at 320 mg/kg for 5 days proved to be the slowest with a t(1/2) of about 5 days in the liver and 16 days in the bone marrow. To conclude, evaluation of the cidal kinetics of the different antileishmanial reference drugs revealed striking differences in their parasite elimination half-lives. This BLI approach also enables an in-depth pharmacodynamic comparison between novel drug leads and may constitute an essential tool for the design of potential drug combinations.

Authors: S. Hendrickx, P. B. Feijens, F. Escudie, E. Chatelain, L. Maes, G. Caljon

Date Published: 14th Jun 2024

Publication Type: Journal Article

The urgent need for designing greener drugs

Abstract

Not specified

Authors: Tomas Brodin, Michael G. Bertram, Kathryn E. Arnold, Alistair B. A. Boxall, Bryan W. Brooks, Daniel Cerveny, Manuela Jörg, Karen A. Kidd, Unax Lertxundi, Jake M. Martin, Lauren T. May, Erin S. McCallum, Marcus Michelangeli, Charles R. Tyler, Bob B. M. Wong, Klaus Kümmerer, Gorka Orive

Date Published: 5th Jun 2024

Publication Type: Journal Article

Novel quinoline derivatives with broad-spectrum antiprotozoal activities.

Abstract (Expand)

Several quinoline derivatives incorporating arylnitro and aminochalcone moieties were synthesized and evaluated in vitro against a broad panel of trypanosomatid protozoan parasites responsible for … sleeping sickness (Trypanosoma brucei rhodesiense), nagana (Trypanosoma brucei brucei), Chagas disease (Trypanosoma cruzi), and leishmaniasis (Leishmania infantum). Several of the compounds demonstrated significant antiprotozoal activity. Specifically, compounds 2c, 2d, and 4i displayed submicromolar activity against T. b. rhodesiense with half-maximal effective concentration (EC(50)) values of 0.68, 0.8, and 0.19 microM, respectively, and with a high selectivity relative to human lung fibroblasts and mouse primary macrophages ( approximately 100-fold). Compounds 2d and 4i also showed considerable activity against T. b. brucei with EC(50) values of 1.4 and 0.4 microM, respectively.

Authors: C. B. Hartman, P. S. Dube, L. J. Legoabe, N. Van Pelt, A. Matheeussen, G. Caljon, R. M. Beteck

Date Published: 3rd Jun 2024

Publication Type: Journal Article

One Health

Abstract

Not specified

Authors: Michael G. Bertram, Maria Paola Costi, Eli S.J. Thoré, Tara Sabo-Attwood, Bryan W. Brooks

Date Published: 1st Jun 2024

Publication Type: Journal Article

Proteomic Profiling of Antimalarial Plasmodione Using 3‐Benz(o)ylmenadione Affinity‐Based Probes

Abstract (Expand)

AbstractUnderstanding the mechanisms of drug action in malarial parasites is crucial for the development of new drugs to combat infection and to counteract drug resistance. Proteomics is a widely used … approach to study host‐pathogen systems and to identify drug protein targets. Plasmodione is an antiplasmodial early‐lead drug exerting potent activities against young asexual and sexual blood stages in vitro with low toxicity to host cells. To elucidate its molecular mechanisms, an affinity‐based protein profiling (AfBPP) approach was applied to yeast and P. falciparum proteomes. New (pro‐) AfBPP probes based on the 3‐benz(o)yl‐6‐fluoro‐menadione scaffold were synthesized. With optimized conditions of both photoaffinity labeling and click reaction steps, the AfBPP protocol was then applied to a yeast proteome, yielding 11 putative drug‐protein targets. Among these, we found four proteins associated with oxidoreductase activities, the hypothesized type of targets for plasmodione and its metabolites, and other proteins associated with the mitochondria. In Plasmodium parasites, the MS analysis revealed 44 potential plasmodione targets that need to be validated in further studies. Finally, the localization of a 3‐benzyl‐6‐fluoromenadione AfBPP probe was studied in the subcellular structures of the parasite at the trophozoite stage.

Authors: Ilaria Iacobucci, Vittoria Monaco, Agnès Hovasse, Baptiste Dupouy, Rodrigue Keumoe, Bogdan Cichocki, Mourad Elhabiri, Brigitte Meunier, Jean‐Marc Strub, Maria Monti, Sarah Cianférani, Stéphanie A. Blandin, Christine Schaeffer‐Reiss, Elisabeth Davioud‐Charvet

Date Published: 28th May 2024

Publication Type: Journal Article

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