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92 Publications visible to you, out of a total of 92
The Drug Design & Development Seminar 2026: joining forces with the European Cost Action ‘OneHealthDrugs’

Abstract

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Authors: Simone Haeberlein, Christoph G. Grevelding, Franco H. Falcone, Paul M. Selzer

Date Published: 1st Jul 2026

Publication Type: Journal Article

Synthesis and Evaluation of Nitroheterocyclic Aromatic Adamantanohydrazones with Trypanocidal Activity. Part III

Abstract

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Authors: Angeliki-Sofia Foscolos, Konstantina Stavropoulou, Nuno Santarém, Anabela Cordeiro da Silva, Martin C. Taylor, Theodora Calogeropoulou, Andrew Tsotinis, Ioannis P. Papanastasiou, John M. Kelly, Susan Wyllie

Date Published: 17th Jun 2026

Publication Type: Journal Article

Synthesis of Methoxylated Benzoxanthones as Drug Metabolites of Antischistosomal Schistodiones—A Limited Environmental Risk

Abstract (Expand)

In the search for new antischistosomal 3-benzylmenadiones (benzylMDs), the screening of a library developed in our laboratory led to the identification of two regioisomeric analogues, the 2′,5′- and … 3′,5′-dimethoxy-benzylMD—designated schistodiones A2′,5′ and A3′,5′—which were investigated for their activity against the platyhelminth Schistosoma mansoni and various protozoan parasites, bacteria, and fungi. Reported work has shown that benzylMDs act as prodrugs: their bioactivation undergoes a cascade of redox reactions within the parasite, generating multiple drug metabolites, e.g., the main benzoylmenadione (benzoylMD) intermediates, and reactive oxygen species that interfere with key metabolic pathways. Among the secondary metabolites, benzoxanthones have been identified as potential products generated along this oxidative pathway. The aim of the study was to synthetize methoxylated benzoxanthones, as putative metabolites generated from these antischistosomal benzylMDs. During the synthetic work, several difficulties arose, including the absence of starting reagents, the incompatibility of certain reactions with methoxy groups, the possible formation of several isomers, and the easy re-oxidation of sensitive intermediates. To overcome these obstacles, we developed a new retrosynthetic strategy using modified precursors: replacing methoxy groups with O-methylenemethoxy (OMOM) groups that are more stable in basic media, using aldehydes or aromatic esters as precursors, and replacing certain substituents with groups that are easier and less costly to introduce (chlorine or nitro). Selected metabolites (benzoylMDs, benzoxanthones) were then tested in parasite and cellular assays. Furthermore, benzoylMDs were tested as subversive substrates of S. mansoni thioredoxin-glutathione reductase (SmTGR) and selected drug metabolites were investigated in SmTGR modeling experiments. From a One Health perspective, these benzylMD derivatives pose limited environmental risk because their metabolites lack toxicity when encountered externally, as toxicity requires intracellular metabolic activation and localized formation of reactive intermediates in close proximity to their cellular targets inside parasites.

Authors: Elena Cesar-Rodo, Jeremy Boilevin, Jimmy Richard, Peter D. Ziniel, Didier Belorgey, Louis Maes, Francesco Angelucci, David Lee Williams, Elisabeth Davioud-Charvet, Don Antoine Lanfranchi

Date Published: 27th May 2026

Publication Type: Journal Article

Environmentally Safe and Just Pharmacy: A Framework and Action Plan for Operating within the Earth System Boundary for Novel Entities

Abstract

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Authors: Alistair B. A. Boxall, Priyanie Amerasinghe, Sally Beckenham, Michael G. Bertram, Sally Gaw, Austin D. Gray, Karen A. Kidd, Laura M. Langan, Kenneth M. Y. Leung, Jack L. Manera, Karina S. B. Miglioranza, Rik Oldenkamp, Bryan W. Brooks

Date Published: 7th May 2026

Publication Type: Journal Article

A strategic discovery roadmap towards high-quality leads and drug development candidates for kinetoplastid diseases. Part 3: from lead towards a drug development candidate

Abstract (Expand)

Abstract Neglected tropical diseases such as leishmaniasis, Chagas disease, sleeping sickness and animal trypanosomiasis remain a significant global health challenge. This part of the roadmap outlines …e roadmap outlines a streamlined path for progressing from lead identification to a drug development candidate, tailored to the specific needs of kinetoplastid infections. Besides the medicinal upscaling of synthesis, this review highlights key experiments in pharmacology in non-rodent species, toxicology, pharmacokinetics and pharmaceutics. These include but are not limited to early evaluation of safety using refined in vitro and in vivo methods to enhance predictive value, bioavailability and distribution to target tissues, and formulation strategies leveraging various delivery systems to optimize efficacy and safety. Environmental toxicity is also addressed proactively, for which in silico tools are presented. Collectively, this roadmap provides a practical, scalable approach to deliver high-quality drug candidates capable of addressing the urgent needs for kinetoplastid diseases (Figure 1).

Authors: Sarah Hendrickx, Kayhan Ilbeigi, Eli S J Thoré, Michael G Bertram, Estefanía Calvo-Alvarez, Sener Cintesun, Ana Isabel Olías-Molero, María Jesús Corral, Marta Mateo-Barrientos, Jérôme Estaquier, Sébastien Pomel, José María Alunda, Sheraz Gul, Katrien Van Bocxlaer, Frédéric Frézard, Joana Tavares, Anabela Cordeiro Da Silva, Maria Paola Costi, Louis Maes, Guy Caljon

Date Published: 5th May 2026

Publication Type: Journal Article

The EamA metabolite transporter does not affect antileishmanial drug susceptibility.

Abstract (Expand)

Leishmaniasis is a major neglected tropical disease, exists in 98 countries and constitutes a global public health threat. As chemotherapy is confronted with drug resistance and treatment failure, … understanding the underlying mechanisms and continued drug discovery efforts are needed in the fight against leishmaniasis. A previous cosmid-based overexpression study suggested a role for EamA (LINF_020008400), annotated as a putative drug-metabolite transporter, in resistance to novel antileishmanial oxaboroles. To assess fitness cost and drug susceptibility, gene deficient Leishmania infantum lines were generated using CRISPR-Cas9 gene editing and overexpression from the ssu locus was achieved using the pLEXSY system. While in vitro parasite growth and survival were unchanged compared to control lines, the intracellular burden of the null mutant was lower. In vitro exposure to current antileishmanial drugs and several novel leads revealed an unchanged drug sensitivity profile in extracellular and intramacrophage assays. Similarly, the overexpression lines showed a significantly lower infection rate, but their drug susceptibility profiles showed no significant differences from the control. Collectively, these data suggest that -under the tested conditions- LINF_020008400 is not essential for parasite fitness, host cell infectivity and survival following exposure to antiparasitic drugs.

Authors: R. Ahmad, G. Gastoldi, S. T. Wong, A. Baeza Garcia, G. Caljon

Date Published: 19th Apr 2026

Publication Type: Journal Article

A strategic discovery roadmap towards high-quality leads and drug development candidates for kinetoplastid diseases. Part 1: setting the stage

Abstract (Expand)

Abstract Given the impact of kinetoplastid diseases, the limited therapeutic options and risk of treatment failure, continued research efforts to discover novel drug entities are required. The ambition …ired. The ambition to deliver drug development candidates has mainly been taken on board by academia and public private partnerships, but remains highly challenging because of the lack of adequate funding and standardized laboratory procedures. Establishing a systematic roadmap of experiments and decision criteria to attain high-quality leads and drug candidates with lower risk profiles remains the logical path to deliver more compelling proof-of-concepts for impactful diseases, such as African trypanosomiasis, Chagas disease and visceral and cutaneous leishmaniasis. In a three-part series, a structured roadmap from ‘hit finding’ to ‘drug development candidate’ is presented with a focus on the minimal essential data package, laboratory experimental models and endpoints. Part 1 introduces the concept of a pragmatic framework with reference to specific preclinical R&D stages: (i) hit finding, (ii) hit profiling, (iii) lead definition and (iv) drug development candidate to support a more focused early development path that remains accessible to engaged stakeholders. The experiment-oriented roadmap is presented in the next parts addressing the discovery and characterization of confirmed hits (Part 2) and the lead discovery phase towards identification of a drug development candidate (Part 3). Although specifically focusing on kinetoplastid diseases, the principles also apply to small-molecule preclinical R&D against other microbial diseases, evidently with specific adaptation of the primary pharmacology models.

Authors: Sarah Hendrickx, Kayhan Ilbeigi, Eli S J Thoré, Michael G Bertram, Estefanía Calvo-Alvarez, Sener Cintesun, Ana Isabel Olías-Molero, María Jesús Corral, Marta Mateo-Barrientos, Jérôme Estaquier, Sébastien Pomel, José María Alunda, Sheraz Gul, Katrien Van Bocxlaer, Frédéric Frézard, Joana Tavares, Anabela Cordeiro Da Silva, Maria Paola Costi, Louis Maes, Guy Caljon

Date Published: 3rd Apr 2026

Publication Type: Journal Article

The application of ultrastructure expansion microscopy reveals the apical microtubule architecture of Babesia

Abstract

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Authors: Viktoriya Levytska, Alexey Bondar, Ana Maria Filipe, Jana Kopecka, Daniel Sojka, Marie Jalovecka

Date Published: 1st Apr 2026

Publication Type: Journal Article

Multifaceted biological and computational assessment of aromatic and N-heteroaromatic non-substituted thiosemicarbazones.

Abstract (Expand)

Thiosemicarbazones (TSCs) constitute a pharmacologically versatile class of compounds with documented antimicrobial, antiviral, and anticancer properties. Despite their therapeutic potential, their … biological mechanisms and pharmacokinetic behaviour remain insufficiently characterized. In this study, we investigated the biological activity of the library consisting of 28 aromatic and heteroaromatic compounds against twelve cancer cell and two normal cell lines, and four parasites. Six N-heteroaromatic thiosemicarbazones based on pyridine (13, 14, and 18), quinoline (24 and 26), and indole (27) moieties show promising anticancer and/or antiparasitic activity. Density functional theory (DFT) calculations indicated that the biological activity of 13, 14, 18, 24, and 26 arises from their ability to chelate d-metals, whereas 27 operates via a distinct mechanism. The passive gastrointestinal absorption and Human serum albumin (HSA) binding ability of these six compounds were evaluated by the Parallel artificial membrane permeability (PAMPA) technique and high-performance affinity chromatography, respectively. Compound 26 emerged as the most potent and selective anticancer agent and was further examined through cell cycle profiling, caspase-3/7 activation, DNA double-strand break quantification, 3D spheroid assays, and an in ovo chorioallantoic membrane (CAM) model, supported by HSA docking and molecular dynamics simulations. Collectively, our results indicate that 26 is a selective anticancer agent that exerts cytotoxic effects preferentially in cancer cells, by inducing apoptosis and DNA double-strand breaks.

Authors: N. Macijewska, P. Ristic, A. Kallingal, M. Gulea, M. Donnard, N. Girard, A. Matheeussen, N. Van Pelt, G. Caljon, V. Dobricic, J. Boskovic, M. Popovic-Nikolic, K. Nikolic, M. Zloh, V. Blagojevic, T. Todorovic, N. Filipovic

Date Published: 25th Mar 2026

Publication Type: Journal Article

A strategic discovery roadmap towards high-quality leads and drug development candidates for kinetoplastid diseases. Part 2: from molecule to confirmed hit

Abstract (Expand)

Abstract Given the medical importance and challenges related to kinetoplastid diseases, a strategic roadmap is needed for the identification of high-quality leads and drug development candidates. Within …candidates. Within the aim to deliver more compelling proof-of-concept read-outs, this part proposes a systematic flow-chart of laboratory experiments and decision criteria, focusing on African trypanosomiasis, Chagas disease and visceral and cutaneous leishmaniasis. Next to precision experimental design and reporting, an overview is provided of various complementary laboratory models reproducing kinetoplastid infection and disease. Technical aspects of conventional in vitro and in vivo approaches and, more recently, in silico methods are presented with reference to specific preclinical R&D stages from ‘hit finding’ to ‘profiling of a confirmed hit’, covering the expertise areas of medicinal chemistry, primary pharmacology, (eco)toxicology, pharmacokinetics and pharmaceutics (Figure 1).

Authors: Sarah Hendrickx, Kayhan Ilbeigi, Eli S J Thoré, Michael G Bertram, Estefanía Calvo-Alvarez, Sener Cintesun, Ana Isabel Olías-Molero, María Jesús Corral, Marta Mateo-Barrientos, Jérôme Estaquier, Sébastien Pomel, José María Alunda, Sheraz Gul, Katrien Van Bocxlaer, Frédéric Frézard, Joana Tavares, Anabela Cordeiro Da Silva, Maria Paola Costi, Louis Maes, Guy Caljon

Date Published: 4th Mar 2026

Publication Type: Journal Article

Cytotoxicity and Antimicrobial Activity of GaMF1 Analogs.

Abstract (Expand)

Recent studies have identified the mycobacterial adenosine triphosphate synthase inhibitor GaMF1 and its structural analogs as compounds with noteworthy antituberculosis activity. Despite these promising … results, a significant limitation remains their cytotoxicity against human cells, which, in its current state, overshadows the therapeutic potential. Therefore, addressing this off-target toxicity is essential for the further development of these compounds as viable drug candidates. In this study, we systematically explored structural modifications of the original GaMF1 scaffold with the primary aim of reducing its inherent cytotoxicity. Individual regions of the parent structure were progressively replaced, enabling the identification of substituents that effectively attenuate cytotoxic effects. Importantly, these structural refinements also led to the emergence of pronounced antiparasitic activity, particularly against trypanosomal species such as Trypanosoma cruzi, Trypanosoma brucei brucei, and Trypanosoma brucei rhodesiense. These findings suggest that the biological potential of this compound class extends beyond what has previously been described. Furthermore, we evaluated the cytotoxicity of selected derivatives against a panel of tumor cell lines, where some compounds showed encouraging antiproliferative effects.

Authors: J. Chasak, P. Vyvlecka, I. Nemec, A. Matheeussen, N. Van Pelt, P. Cos, G. Caljon, V. Krystof, L. Brulikova

Date Published: 25th Feb 2026

Publication Type: Journal Article

The heme A synthase Cox15, as a target of redox-active 3-benzylmenadiones with antiparasitic activity

Abstract (Expand)

ABSTRACT Chagas disease, caused by Trypanosoma cruzi , is a neglected parasitic infection. The very limited arsenal of anti- T . cruzi treatments calls for the development of new drugs. Recently, a …sitic infection. The very limited arsenal of anti- T . cruzi treatments calls for the development of new drugs. Recently, a library of 3-benzylmenadione derivatives was synthesized, with cruzidione being the most efficient and specific compound against the parasite. To decipher its mode of action, we used the yeast Saccharomyces cerevisiae as a model. Evidence pinpointed at the heme A synthase Cox15 as a primary target of cruzidione: (i) a mutation in Cox15 (i.e., S429F) renders the yeast cells highly sensitive to the drug, (ii) treatment with cruzidione led to the loss of cytochrome c oxidase, an enzyme that relies on heme A as an essential cofactor, and (iii) replacement of the yeast Cox15 by T. cruzi enzyme resulted in a high sensitivity to cruzidione. We then investigated the effect of cruzidione in T. cruzi and observed a significant reduction in the heme contents, most likely involving the inhibition of the heme A synthase. This, in turn, led to a decrease in O 2 consumption by the parasite. Finally, using the yeast model, we showed that, similar to what we previously found for the antimalarial benzylmenadione plasmodione, NADH-dehydrogenase plays a key role in cruzidione bioactivation. We proposed that the reduced benzoylmenadione metabolites, produced by the reaction with NADH-dehydrogenase, act as Cox15 inhibitors. This study, through the identification of the mode of action of cruzidione, highlighted Cox15 as a novel target for antiparasitic drugs.

Authors: Marcelo L. Merli, Claudia Serot, Cindy Vallières, Julia A. Cricco, Bogdan I. Iorga, Elisabeth Davioud-Charvet, Brigitte Meunier

Date Published: 7th Jan 2026

Publication Type: Journal Article

Oxyprenyl–chalcones as antibacterial hits: design of experiments-optimized synthesis, antibacterial evaluation, early drug-like profiling and biodegradability prediction

Abstract

The escalating threat of antimicrobial resistance (AMR) compels the development of novel antibiotics with broad spectrum activity and environmentally responsible degradation profiles.

Authors: Ludovica Marotta, Francesca Maria Pia Rita Giammarino, Brondon Brandly Senenou Tambou, Valeria Tudino, Stefania Butini, Lorenza Broccardo, Sacha Michèle Idriss Cancade, Jean-Denis Docquier, Federica Perego, Nicoletta Basilico, Lorenzo Raffellini, Sheraz Gul, Gabriele Carullo, Sandra Gemma, Giuseppe Campiani

Date Published: 2026

Publication Type: Journal Article

Syntheses and computational analyses of selected macrolide derivatives derived from clarithromycin A

Abstract (Expand)

This study presents the synthesis and experimental and computational analysis of novel macrolide derivatives obtained from clarithromycin A, with the aim of exploring their potential to address the … growing problem of antimicrobial resistance. The compounds synthesized include 2?-O-acetyl-clarithromycin A, its phosphoramidite derivative, and the corresponding phosphonyl derivative. Special attention was paid to the optimization of phosphitylation conditions due to the inherent instability of phosphoramidite compounds. The purity of the phosphoramidite derivative was successfully confirmed using diffusion-ordered NMR spectroscopy (DOSY). Comprehensive conformational analyses were carried out using molecular modeling techniques, followed by molecular docking and MM-GBSA calculations with a target protein from Escherichia coli to evaluate the relative binding affinities of clarithromycin A and its derivatives. The results indicate that the phosphoramidite and phosphonyl derivatives exhibit comparable binding affinities relative to the parent antibiotic. In addition, complex mass spectrometric fragmentation patterns of the phosphorus-containing derivatives were analyzed and rationalized using the MS Fragmenter computational tool.

Authors: Biljana Arsic, Gareth Morris, Abdolreza Hassanzadeh, Olga Jovanovic, Jill Barber, Djordje Glisin

Date Published: 2026

Publication Type: Journal Article

Synthesis and evaluation of nitroheterocyclic aromatic adamantane amides with trypanocidal activity. Part II

Abstract

New nitroheterocyclic adamantane amides display promising trypanocidal activity. The spacer length between the adamantylphenyl backbone and the nitroheterocyclic ring plays a crucial role in potency.

Authors: Angeliki-Sofia Foscolos, Richard L. Atherton, Maria Billia, Markos-Orestis Georgiadis, Nuno Santarém, Anabela Cordeiro da Silva, Martin C. Taylor, John M. Kelly, Theodora Calogeropoulou, Andrew Tsotinis, Thomas Mavromoustakos, Ioannis P. Papanastasiou

Date Published: 2026

Publication Type: Journal Article

Are Behavioral Ecotoxicity Endpoints Relevant at the Population Level? Evidence-Based Insights for Environmental Protection

Abstract

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Authors: Michael G. Bertram, Marlene Ågerstrand, Sigal Balshine, Jack A. Brand, Bryan W. Brooks, ZhiChao Dang, Alex T. Ford, Henner Hollert, Matthew K. LeFauve, Jack L. Manera, Jake M. Martin, Marcus Michelangeli, Maria Moiron, Eleanor R. Moore, Holly J. Puglis, Andrew Sih, Jeffery A. Steevens, Eli S. J. Thoré, Bob B. M. Wong, Lauren Zink, Tomas Brodin

Date Published: 24th Dec 2025

Publication Type: Journal Article

From pan-active to parasite-selective antiparasitic agents: A scaffold hopping approach

Abstract

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Authors: Chiara Borsari, Nuno Santarem, Dina Coertzen, Asia Mazzolari, Alexandra Ioana Corfu, Catarina Coelho, Francisca Barbosa, Lucia Tamborini, Lyn-Marié Birkholtz, Lorenzo Raffellini, Oliver Keminer, Nicoletta Basilico, Silvia Parapini, Sheraz Gul, Anabela Cordeiro-da-Silva, Paola Conti

Date Published: 1st Dec 2025

Publication Type: Journal Article

Thiazolidinones and related analogues as efficient antitrypanosomal agents.

Abstract (Expand)

We designed and synthesised a series of thiazolidinediones and related analogues and evaluated their antiparasitic activity. A structure-activity relationship (SAR) study focused on modifications of … specific parts of the molecule revealed derivatives that displayed significant activity against Trypanosoma brucei species. Notably, the analogue 6i exhibited exceptional activity, with an EC(50) value of 30 nM and a selectivity index of >2000, against the protozoan Trypanosoma brucei rhodesiense, which causes human African trypanosomiasis. Additionally, compounds 6a, 6k, 7e, and 18 demonstrated antitrypanosomal activities in the less than 5 muM range. Our most active analogue 6i represents a promising candidate for further preclinical development.

Authors: M. Kolarik, K. Ilbeigi, G. Caljon, L. Brulikova

Date Published: 1st Dec 2025

Publication Type: Journal Article

Persistent myeloid cell reprogramming despite miltefosine treatment in leishmania-infected macaques

Abstract

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Authors: Morgane Picard, Steven Boutrais, Vasco Rodrigues, Yasmina Fortier, Chloé Borde, Calaiselvy Soundaramourty, Julien Clain, Charles Joly-Beauparlant, Gina Racine, Ouafa Zghidi-Abouzid, Arnaud Droit, Alain Pruvost, Maria Paola Costi, Ricardo Silvestre, Anabela Cordeiro da Silva, Jane MacDougall, Sónia André, Jérôme Estaquier

Date Published: 1st Dec 2025

Publication Type: Journal Article

Π-Π stacking stabilized polymeric micelles for hydrophobic drug delivery in the treatment of leishmaniasis

Abstract

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Authors: Ana G. Gomes-Alves, Aida Varela-Moreira, Tânia Cruz, Margarida Duarte, Helena Castro, Rui Moreira, Ana S. Ressurreição, Gert Storm, Wim E. Hennink, Ana M. Tomás

Date Published: 1st Dec 2025

Publication Type: Journal Article

Design of 2-Aminobenzothiazole Derivatives Targeting Trypanosomatid PTR1 by a Multidisciplinary Fragment Hybridization Approach.

Abstract (Expand)

Pteridine reductase 1 (PTR1) is a folate pathway enzyme essential for pathogenic trypanosomatids and a promising drug target for diseases such as sleeping sickness and leishmaniasis. Previous studies … have shown that the 2-aminobenzothiazole moiety targets the PTR1 biopterin pocket, while 3,4-dichlorophenyl-containing compounds, such as I bind a different region of the Trypanosoma brucei PTR1 (TbPTR1) pocket. This study combines both moieties via various linkers, creating two compound series screened in silico against TbPTR1 and Leishmania major PTR1 (LmPTR1). In the first series, five compounds were synthesized, and 1a and 1b emerged as potent TbPTR1 inhibitors, with 1b also being active against LmPTR1 and moderately effective against Leishmania infantum. Furthermore, structure-activity relationship analysis, supported by quantum calculations and crystallography, revealed meta-halogenation to be more favorable than para, although single halogenation reduced antiparasite effects. Our fragment hybridization approach led to less toxic, more effective compounds than I.

Authors: J. Panecka-Hofman, P. Linciano, I. Pohner, E. Dyguda-Kazimierowicz, W. Jedwabny, G. Landi, N. Santarem, G. Witt, B. Ellinger, M. Kuzikov, R. Luciani, S. Ferrari, D. Aiello, S. Mangani, C. Pozzi, A. Cordeiro-da-Silva, S. Gul, M. P. Costi, R. C. Wade

Date Published: 9th Oct 2025

Publication Type: Journal Article

Long-Circulating Liposomes Codelivering Amphotericin B and Retinoic Acid for Cutaneous Leishmaniasis Treatment

Abstract

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Authors: Thais T. Santos, Eduardo B. Lages, Tiago N. Q. Ricotta, Leandro G. de Oliveira, Guilherme S. Ramos, Julie Burlot, Sonia Abreu, Pierre Chaminade, François-Xavier Legrand, Pauline Tran, Claudine Deloménie, Virgínia M. R. Vallejos, Doumet Georges Helou, Raquel M. de Almeida, Celso M. Queiroz-Junior, Gabriel B. M. Teobaldo, Cristiano L. P. de Oliveira, Lucas A. M. Ferreira, Marta M. G. Aguiar, Sébastien Pomel, Frédéric Frézard

Date Published: 7th Oct 2025

Publication Type: Journal Article

AgamOBP1‐Directed Discovery of Repellents to Control the Spread of Mosquito‐Borne Diseases

Abstract (Expand)

Toward the discovery of novel efficient repellents, protein‐directed dynamic combinatorial chemistry (pdDCC) coupled to saturation‐transfer difference (STD) NMR spectroscopy was initially employed to … identify modulators of the malaria vector Anopheles gambiae Odorant Binding Protein 1 (AgamOBP1). A library of potential binders of AgamOBP1 (secondary amines) generated from two amines and seven aldehydes was designed aiming to enable interactions with critical amino acids at the DEET‐site and to bridge the DEET‐ and Icaridin sIC‐binding pockets, both implicated in repellents recognition. Solubility issues hindered the clear identification of binders among the DCL members, except for one sublibrary, leading us to shift our strategy towards the synthesis of the designed amines, followed by direct evaluation of their binding to AgamOBP1 using 1 H STD NMR spectroscopy. The identified binders were further validated in vitro by fluorescence competition assays, and the most potent compounds which also possessed suitable vapor pressure were evaluated as repellents in arm‐in‐cage behavioral assays against Aedes albopictus . Amines 2A , 3A , 4A , and 6A showed significant repellent activity. The most potent was compound 4A (4‐methyl‐ N ‐(pyridin‐4‐ylmethyl)aniline) which acted as a a DEET‐like repellent at 0.4 μL cm − 2 dose. Thus, our strategy showcased a promising scaffold for further optimization toward efficient mosquito repellents.

Authors: Evanthia Chazapi, Eftichia Kritsi, Constantinos Potamitis, Panagiota G. V. Liggri, Katerina E. Tsitsanou, Christina E. Drakou, Antonios Michaelakis, Dimitrios P. Papachristos, Spyros E. Zographos, Maria Zervou, Theodora Calogeropoulou

Date Published: 21st Sep 2025

Publication Type: Journal Article

Sustainable Antiparasitic Agents from an Agro-Industrial Waste: Mitochondria-Targeting Cashew Nutshell Liquid-Derived Phosphonium and Ammonium Salts

Abstract

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Authors: Bianca Martinengo, Cecilia Baldassarri, Kayhan Ilbeigi, Hamed E. Alkhalaf, Aditya Sarode, Ehab Kotb Elmahallawy, Ba Reum Kwon, Amos Sarpong Agyei, Aigerim Abdimanova, Ludmila Ferreira de Almeida Fiuza, Raquel Azevedo, Ketlym da Conceição, Marcos Meuser Batista, Ellyêssa Nascimento Borges, Kleber Santiago Freitas e Silva, Éder Jéferson Souza Cardoso, Natália Cipriano Monteiro, Lais Flavia Nunes Lemes, Luiz Antonio Soares Romeiro, Antonio Alonso, Maria de Nazaré Correia Soeiro, Guy Caljon, Bryan W. Brooks, Harry P. De Koning, Maria Laura Bolognesi

Date Published: 8th Sep 2025

Publication Type: Journal Article

Drug Repurposing for Kala-Azar

Abstract (Expand)

Objective: Visceral leishmaniasis (VL), a Neglected Tropical Disease caused by Leishmania donovani, remains insufficiently addressed by current therapies due to high toxicity, poor efficacy, and … immunosuppressive complications. This study aimed to identify and characterize repurposed drugs that simultaneously target parasite-encoded and host-associated mechanisms essential for VL pathogenesis. Methods: Two complementary in silico drug repurposing strategies were employed. The first method utilized electron–ion interaction potential (EIIP) screening followed by molecular docking and molecular dynamics (MD) simulations targeting two L. donovani proteins: Rab5a and pteridine reductase 1 (PTR1). The second approach employed network-based drug repurposing using the Drugst.One platform, prioritizing candidates via STAT3-associated gene networks. Predicted drug–target complexes were validated by 100 ns MD simulations, and pharmacokinetic parameters were assessed via ADMET profiling using QikProp v7.0 and SwissADME web server. Results: Entecavir and valganciclovir showed strong binding to Rab5a and PTR1, respectively, with Glide Scores of −9.36 and −9.10 kcal/mol, and corresponding MM-GBSA ΔG_bind values of −14.00 and −13.25 kcal/mol, confirming their stable interactions and repurposing potential. Network-based analysis identified nifuroxazide as the top candidate targeting the host JAK2/TYK2–STAT3 axis, with high stability confirmed in MD simulations. Nifuroxazide also displayed the most favorable ADMET profile, including oral bioavailability, membrane permeability, and absence of PAINS alerts. Conclusions: This study highlights the potential of guanine analogs such as entecavir and valganciclovir, and the nitrofuran derivative nifuroxazide, as promising multi-target drug repurposing candidates for VL. Their mechanisms support a dual strategy targeting both parasite biology and host immunoregulation, warranting further preclinical investigation.

Authors: Biljana Arsić, Budimir S. Ilić, Andreas Maier, Michael Hartung, Jovana Janjić, Jelena Milićević, Jan Baumbach

Date Published: 6th Aug 2025

Publication Type: Journal Article

Human Dialyzable Leukocyte Extract Enhances Albendazole Efficacy and Promotes Th1/Th2-Biased Lymphocyte and Antibody Responses in Peritoneal Cavity of Murine Model of Mesocestoides vogae Infection

Abstract (Expand)

Human leukocyte extract (HLE), a non-immunogenic dialyzable leukocyte preparation (<10 kDa), may serve as a safe adjuvant in immunotherapy. We investigated the effects of albendazole (ABZ), HLE, and … their combination in Mesocestoides vogae infected mice, focusing on lymphoid cells in the peritoneal cavity, the site of larval proliferation and parasite-induced immunosuppression. Peritoneal lymphoid cells were analysed by flow cytometry and qPCR. Cells proliferative responses to ConA, LPS, and parasite excretory/secretory (E/S) antigens, cytokine production (ELISA), IgM and IgG isotypes in exudates and parasite antigen recognition (Western blot) were assessed. Efficacy was measured by larval burden and 14-3-3 gene expression in larvae. HLE combined with ABZ enhanced larval clearance and suppressed 14-3-3 gene expression in larvae. HLE and combination therapy increased CD3+ T cell frequencies, especially CD3+high, reduced regulatory CD3+/IL-10 Tregs and expression of Foxp3+. All treatments diminished CD19+/IL-10+ Bregs, correlating with lower CD9 and Atf3 mRNA levels compared to infected mice. Transcription factors T-bet expression was strongly upregulated, while GATA3 was moderately elevated. IFN-γ production and T/B cell proliferation were restored after HLE and combination therapy, partially, even in the presence of E/S antigens. IgM and total IgG levels against parasite antigens declined, while Th1-associated IgG2a increased in ABZ+HLE and HLE-treated groups. Albendazole failed to reverse the immunosuppressive Treg-type immunity but was more effective in reducing Breg populations and their functions. HLE enhanced ABZ efficacy by restoring Th1 responsiveness, reducing Treg/Breg activity, and modulating antibody profiles. It represents a promising immunomodulatory adjuvant in the treatment of the infections associated with Th2/Treg-driven immunosuppression.

Authors: Gabriela Hrčková, Dagmar Mudroňová, Katarína Reiterová, Serena Cavallero, Ilaria Bellini

Date Published: 21st Jul 2025

Publication Type: Journal Article

Uncovering the Unusual Inhibition Mechanism of a Trypanosome Alternative Oxidase Inhibitor Displaying Broad-Spectrum Activity against African Animal Trypanosomes

Abstract

Not specified

Authors: Godwin U. Ebiloma, Emmanuel O. Balogun, Natsumi Arai, Momoka Otani, Cecilia Baldassarri, Amani Alhejely, Eduardo Cueto-Díaz, Harry P. De Koning, Christophe Dardonville, Tomoo Shiba

Date Published: 4th Jun 2025

Publication Type: Journal Article

Design, Synthesis and Antiplasmodial Activities of a Library of Fluorine-Based 3-Benzylmenadiones

Abstract (Expand)

Plasmodione is a potent early antiplasmodial compound. A metabolic study on mice treated with plasmodione revealed that 6-hydroxy–plasmodione was the main metabolite eliminated in the urine of treated … mice. To block the metabolic pathway in the host, the introduction of fluorine at C-6 of the 3-benzylmenadione core was applied and showed potent antiplasmodial activity similar to that of the plasmodione analogue in vitro. In this work, a library of 38 6-fluoro-3-benzylmenadione analogues (a series) was constructed by incorporating structurally diverse groups in place of the 4-(trifluoromethyl) substituent present in the antiplasmodial plasmodione, via three synthetic routes. All new compounds were tested against the P. falciparum NF54 strain and for cytotoxicity with the rat L6 line. With a fluorine atom at C-6, A-a-21 was revealed to be the only compound from the a series, superior to the 6-H- analogue from the b series, with an IC50 value of 70 nM versus 200 nM. Then, five other fluorine-based 3-benzylmenadiones, in which the fluorine was introduced in various positions of the 3-benzylmenadione core, were synthetized to assist our understanding of the impact of fluorine on antiplasmodial potencies in vitro; in particular, the aim here was to compare the effects of human serum and P. berghei species in these drug screens. This was also conducted in vivo with the P. berghei-infected mouse model. In the P. berghei species assay, PD and the 4′-fluoro-3′-trifluoromethyl-benzylmenadione A-b-9 exhibited a similar antiplasmodial behavior toward P. falciparum versus P. berghei. In the human serum versus Albumax assays, only the 6-fluoro–plasmodione showed a lower shift factor between Albumax assays and human serum conditions, suggesting a lower protein binding for the 6-F-PD compared to plasmodione or A-b-9. In vivo, 6-fluoro–plasmodione proved to be the most potent 3-benzylmenadione, reducing parasitemia by 50% after oral administration at 50 mg/kg.

Authors: Matthieu Roignant, Jimmy Richard, Maxime Donzel, Matthias Rottmann, Pascal Mäser, Elisabeth Davioud-Charvet

Date Published: 3rd Jun 2025

Publication Type: Journal Article

Antileishmanial activity of Ptilostemon chamaepeuce subsp. cyprius

Abstract

Not specified

Authors: Chad Schou, Justus Mukavi, Jandirk Sendker, Androulla Miliotou, Vasiliki Christodoulou, Yiannis Sarigiannis, Aleksandar Jovanovic, Thomas J. Schmidt, Panagiotis Karanis

Date Published: 1st May 2025

Publication Type: Journal Article

Synthesis of Tricyclic and Tetracyclic Lactone Derivatives of Thieno[2,3-b]pyrazine or Thieno[2,3-b]quinoline: Preliminary Antitumor and Antiparasitic Activity Evaluation

Abstract (Expand)

Tricyclic and tetracyclic lactone derivatives of thieno[2,3-b]pyrazine or thieno[2,3-b]quinoline, and 2H-pyrones were prepared using different methodologies. Pd/Cu-catalyzed Sonogashira coupling using … Et3N as a base, of methyl 7-bromothieno[2,3-b]pyrazine-6-carboxylate and (het)arylalkynes to yield the Sonogashira ester products, gave also the corresponding tricyclic lactones as minor products. However, the major products did not cyclize with TFA. Tricyclic lactones were then obtained by a tandem one-pot Sonogashira coupling and 6-endo-dig lactonization of 7-bromothieno[2,3-b]pyrazine-6-carboxylic acid with (het)arylalkynes, in good yields. Halogenated tricyclic lactones were synthesized by halocyclization using CuX and NXS. Tetracyclic lactones were synthesized through a Rh(III)-catalyzed formal [4+2] cycloaddition, between thieno[2,3-b]quinoline-2-carboxylic acid and internal alkynes, triggered by C-H activation, with the carboxylic group acting as a directing group. Using the SRB assay, the antitumor activity of both Sonogashira products and lactones was evaluated across five human cancer cell lines (CaCo-2, MCF-7, AGS, HeLa, NCI-H460). The best-performing compound was a Sonogashira product showing a GI50 < 10 µM in all tumor cell lines and low toxicity in PLP2 cells. Additionally, antiparasitic testing against Trypanosoma brucei and Leishmania infantum revealed some compounds with IC50 < 11 µM, though some level of cytotoxicity was observed in THP-1—derived macrophages.

Authors: Maria F. Martins, Francisco Ribeiro, Ana Borges, Ricardo C. Calhelha, Nuno Santarém, Anabela Cordeiro-da-Silva, Maria-João R. P. Queiroz

Date Published: 30th Apr 2025

Publication Type: Journal Article

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