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19 Publications visible to you, out of a total of 19

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

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

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

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

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

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

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 beenctions 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

Abstract

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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

Abstract

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Authors: Alexandra Ioana Corfu, Nuno Santarem, Sara Luelmo, Gaia Mazza, Alessandro Greco, Alessandra Altomare, Giulio Ferrario, Giulia Nasta, Oliver Keminer, Giancarlo Aldini, Lucia Tamborini, Nicoletta Basilico, Silvia Parapini, Sheraz Gul, Anabela Cordeiro-da-Silva, Paola Conti, Chiara Borsari

Date Published: 8th May 2024

Publication Type: Journal Article

Abstract

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Authors: Pasquale Linciano, Cecilia Pozzi, Giusy Tassone, Giacomo Landi, Stefano Mangani, Matteo Santucci, Rosaria Luciani, Stefania Ferrari, Nuno Santarem, Lorenzo Tagliazucchi, Anabela Cordeiro-da-Silva, Michele Tonelli, Donatella Tondi, Laura Bertarini, Sheraz Gul, Gesa Witt, Carolina B. Moraes, Luca Costantino, Maria Paola Costi

Date Published: 2024

Publication Type: Journal Article

Abstract

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Authors: Pasquale Linciano, Antonio Quotadamo, Rosaria Luciani, Matteo Santucci, Kimberley M. Zorn, Daniel H. Foil, Thomas R. Lane, Anabela Cordeiro da Silva, Nuno Santarem, Carolina B Moraes, Lucio Freitas-Junior, Ulrike Wittig, Wolfgang Mueller, Michele Tonelli, Stefania Ferrari, Alberto Venturelli, Sheraz Gul, Maria Kuzikov, Bernhard Ellinger, Jeanette Reinshagen, Sean Ekins, Maria Paola Costi

Date Published: 3rd Nov 2023

Publication Type: Journal Article

Abstract (Expand)

A series of nine novel ether phospholipid-dinitroaniline hybrids were synthesized in an effort to deliver more potent antiparasitic agents with improved safety profile compared to miltefosine. The compounds were evaluated for their in vitro antiparasitic activity against L. infantum, L.donovani, L. amazonensis, L. major and L. tropica promastigotes, L. infantum and L. donovani intracellular amastigotes, Trypanosoma brucei brucei and against different developmental stages of Trypanosoma cruzi. The nature of the oligomethylene spacer between the dinitroaniline moiety and the phosphate group, the length of the side chain substituent on the dinitroaniline and the choline or homocholine head group were found to affect both the activity and toxicity of the hybrids. The early ADMET profile of the derivatives did not reveal major liabilities. Hybrid 3, bearing an 11-carbon oligomethylene spacer, a butyl side chain and a choline head group, was the most potent analogue of the series. It exhibited a broad spectrum antiparasitic profile against the promastigotes of New and Old World Leishmania spp., against intracellular amastigotes of two L. infantum strains and L. donovani, against T. brucei and against T. cruzi Y strain epimastigotes, intracellular amastigotes and trypomastigotes. The early toxicity studies revealed that hybrid 3 showed a safe toxicological profile while its cytotoxicity concentration (CC50) against THP-1 macrophages being >100 μM. Computational analysis of binding sites and docking indicated that the interaction of hybrid 3 with trypanosomatid α-tubulin may contribute to its mechanism of action. Furthermore, compound 3 was found to interfere with the cell cycle in T. cruzi epimastigotes, while ultrastructural studies using SEM and TEM in T. cruzi showed that compound 3 affects cellular processes that result in changes in the Golgi complex, the mitochondria and the parasite’s plasma membrane. The snapshot pharmacokinetic studies showed low levels of 3 after 24 h following oral administration of 100 mg/Kg, while, its homocholine congener compound 9 presented a better pharmacokinetic profile.

Authors: Marina Roussaki, George E. Magoulas, Theano Fotopoulou, Nuno Santarem, Emile Barrias, Ina Pöhner, Sara Luelmo, Pantelis Afroudakis, Kalliopi Georgikopoulou, Paloma Tejera Nevado, Julia Eick, Eugenia Bifeld, María J. Corral, María Dolores Jiménez-Antón, Bernhard Ellinger, Maria Kuzikov, Irini Fragiadaki, Effie Scoulica, Sheraz Gul, Joachim Clos, Kyriakos C. Prousis, Juan J. Torrado, José María Alunda, Rebecca C. Wade, Wanderley de Souza, Anabela Cordeiro da Silva, Theodora Calogeropoulou

Date Published: 1st Sep 2023

Publication Type: Journal Article

Abstract (Expand)

Human African Trypanosomiasis (HAT, sleeping sickness) and Animal African Trypanosomiasis (AAT) are neglected tropical diseases generally caused by the same etiological agent, Trypanosoma brucei. Despite important advances in the reduction or disappearance of HAT cases, AAT represents a risky reservoir of the infections. There is a strong need to control AAT, as is claimed by the European Commission in a recent document on the reservation of antimicrobials for human use. Control of AAT is considered part of the One Health approach established by the FAO program against African Trypanosomiasis. Under the umbrella of the One Health concepts, in this work, by analyzing the pharmacological properties of the therapeutic options against Trypanosoma brucei spp., we underline the need for clearer and more defined guidelines in the employment of drugs designed for HAT and AAT. Essential requirements are addressed to meet the challenge of drug use and drug resistance development. This approach shall avoid inter-species cross-resistance phenomena and retain drugs therapeutic activity.

Authors: Alberto Venturelli, Lorenzo Tagliazucchi, Clara Lima, Federica Venuti, Giulia Malpezzi, George E. Magoulas, Nuno Santarem, Theodora Calogeropoulou, Anabela Cordeiro-da-Silva, Maria Paola Costi

Date Published: 27th Jun 2022

Publication Type: Journal Article

Abstract (Expand)

2-Amino-benzo[ d]thiazole was identified as a new scaffold for the development of improved pteridine reductase-1 (PTR1) inhibitors and anti-trypanosomatidic agents. Molecular docking and crystallography guided the design and synthesis of 42 new benzothiazoles. The compounds were assessed for Trypanosoma brucei and Leishmania major PTR1 inhibition and in vitro activity against T. brucei and amastigote Leishmania infantum. We identified several 2-amino-benzo[ d]thiazoles with improved enzymatic activity ( TbPTR1 IC50 = 0.35 muM; LmPTR1 IC50 = 1.9 muM) and low muM antiparasitic activity against T. brucei. The ten most active compounds against TbPTR1 were able to potentiate the antiparasitic activity of methotrexate when evaluated in combination against T. brucei, with a potentiating index between 1.2 and 2.7. The compound library was profiled for early ADME toxicity, and 2-amino- N-benzylbenzo[ d]thiazole-6-carboxamide (4c) was finally identified as a novel potent, safe, and selective anti-trypanocydal agent (EC50 = 7.0 muM). Formulation of 4c with hydroxypropyl-beta-cyclodextrin yielded good oral bioavailability, encouraging progression to in vivo studies.

Authors: P. Linciano, C. Pozzi, L. D. Iacono, F. di Pisa, G. Landi, A. Bonucci, S. Gul, M. Kuzikov, B. Ellinger, G. Witt, N. Santarem, C. Baptista, C. Franco, C. B. Moraes, W. Muller, U. Wittig, R. Luciani, A. Sesenna, A. Quotadamo, S. Ferrari, I. Pohner, A. Cordeiro-da-Silva, S. Mangani, L. Costantino, M. P. Costi

Date Published: 25th Apr 2019

Publication Type: Journal Article

Abstract (Expand)

According to the World Health Organization, more than 1 billion people are at risk of or are affected by neglected tropical diseases. Examples of such diseases include trypanosomiasis, which causes sleeping sickness; leishmaniasis; and Chagas disease, all of which are prevalent in Africa, South America, and India. Our aim within the New Medicines for Trypanosomatidic Infections project was to use (1) synthetic and natural product libraries, (2) screening, and (3) a preclinical absorption, distribution, metabolism, and excretion-toxicity (ADME-Tox) profiling platform to identify compounds that can enter the trypanosomatidic drug discovery value chain. The synthetic compound libraries originated from multiple scaffolds with known antiparasitic activity and natural products from the Hypha Discovery MycoDiverse natural products library. Our focus was first to employ target-based screening to identify inhibitors of the protozoan Trypanosoma brucei pteridine reductase 1 ( TbPTR1) and second to use a Trypanosoma brucei phenotypic assay that made use of the T. brucei brucei parasite to identify compounds that inhibited cell growth and caused death. Some of the compounds underwent structure-activity relationship expansion and, when appropriate, were evaluated in a preclinical ADME-Tox assay panel. This preclinical platform has led to the identification of lead-like compounds as well as validated hits in the trypanosomatidic drug discovery value chain.

Authors: C. B. Moraes, G. Witt, M. Kuzikov, B. Ellinger, T. Calogeropoulou, K. C. Prousis, S. Mangani, F. Di Pisa, G. Landi, L. D. Iacono, C. Pozzi, L. H. Freitas-Junior, B. Dos Santos Pascoalino, C. P. Bertolacini, B. Behrens, O. Keminer, J. Leu, M. Wolf, J. Reinshagen, A. Cordeiro-da-Silva, N. Santarem, A. Venturelli, S. Wrigley, D. Karunakaran, B. Kebede, I. Pohner, W. Muller, J. Panecka-Hofman, R. C. Wade, M. Fenske, J. Clos, J. M. Alunda, M. J. Corral, E. Uliassi, M. L. Bolognesi, P. Linciano, A. Quotadamo, S. Ferrari, M. Santucci, C. Borsari, M. P. Costi, S. Gul

Date Published: 21st Feb 2019

Publication Type: Journal Article

Abstract (Expand)

Pteridine reductase-1 (PTR1) is a promising drug target for the treatment of trypanosomiasis. We investigated the potential of a previously identified class of thiadiazole inhibitors of Leishmania major PTR1 for activity against Trypanosoma brucei (Tb). We solved crystal structures of several TbPTR1-inhibitor complexes to guide the structure-based design of new thiadiazole derivatives. Subsequent synthesis and enzyme- and cell-based assays confirm new, mid-micromolar inhibitors of TbPTR1 with low toxicity. In particular, compound 4m, a biphenyl-thiadiazole-2,5-diamine with IC50 = 16 muM, was able to potentiate the antitrypanosomal activity of the dihydrofolate reductase inhibitor methotrexate (MTX) with a 4.1-fold decrease of the EC50 value. In addition, the antiparasitic activity of the combination of 4m and MTX was reversed by addition of folic acid. By adopting an efficient hit discovery platform, we demonstrate, using the 2-amino-1,3,4-thiadiazole scaffold, how a promising tool for the development of anti-T. brucei agents can be obtained.

Authors: P. Linciano, A. Dawson, I. Pohner, D. M. Costa, M. S. Sa, A. Cordeiro-da-Silva, R. Luciani, S. Gul, G. Witt, B. Ellinger, M. Kuzikov, P. Gribbon, J. Reinshagen, M. Wolf, B. Behrens, V. Hannaert, P. A. M. Michels, E. Nerini, C. Pozzi, F. di Pisa, G. Landi, N. Santarem, S. Ferrari, P. Saxena, S. Lazzari, G. Cannazza, L. H. Freitas-Junior, C. B. Moraes, B. S. Pascoalino, L. M. Alcantara, C. P. Bertolacini, V. Fontana, U. Wittig, W. Muller, R. C. Wade, W. N. Hunter, S. Mangani, L. Costantino, M. P. Costi

Date Published: 30th Sep 2017

Publication Type: Journal Article

Abstract (Expand)

Flavonoids have previously been identified as antiparasitic agents and pteridine reductase 1 (PTR1) inhibitors. Herein, we focus our attention on the chroman-4-one scaffold. Three chroman-4-one analogues (1-3) of previously published chromen-4-one derivatives were synthesized and biologically evaluated against parasitic enzymes (Trypanosoma brucei PTR1-TbPTR1 and Leishmania major-LmPTR1) and parasites (Trypanosoma brucei and Leishmania infantum). A crystal structure of TbPTR1 in complex with compound 1 and the first crystal structures of LmPTR1-flavanone complexes (compounds 1 and 3) were solved. The inhibitory activity of the chroman-4-one and chromen-4-one derivatives was explained by comparison of observed and predicted binding modes of the compounds. Compound 1 showed activity both against the targeted enzymes and the parasites with a selectivity index greater than 7 and a low toxicity. Our results provide a basis for further scaffold optimization and structure-based drug design aimed at the identification of potent anti-trypanosomatidic compounds targeting multiple PTR1 variants.

Authors: F. Di Pisa, G. Landi, L. Dello Iacono, C. Pozzi, C. Borsari, S. Ferrari, M. Santucci, N. Santarem, A. Cordeiro-da-Silva, C. B. Moraes, L. M. Alcantara, V. Fontana, L. H. Freitas-Junior, S. Gul, M. Kuzikov, B. Behrens, I. Pohner, R. C. Wade, M. P. Costi, S. Mangani

Date Published: 8th Mar 2017

Publication Type: Journal Article

Abstract (Expand)

Flavonoids represent a potential source of new antitrypanosomatidic leads. Starting from a library of natural products, we combined target-based screening on pteridine reductase 1 with phenotypic screening on Trypanosoma brucei for hit identification. Flavonols were identified as hits, and a library of 16 derivatives was synthesized. Twelve compounds showed EC50 values against T. brucei below 10 muM. Four X-ray crystal structures and docking studies explained the observed structure-activity relationships. Compound 2 (3,6-dihydroxy-2-(3-hydroxyphenyl)-4H-chromen-4-one) was selected for pharmacokinetic studies. Encapsulation of compound 2 in PLGA nanoparticles or cyclodextrins resulted in lower in vitro toxicity when compared to the free compound. Combination studies with methotrexate revealed that compound 13 (3-hydroxy-6-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one) has the highest synergistic effect at concentration of 1.3 muM, 11.7-fold dose reduction index and no toxicity toward host cells. Our results provide the basis for further chemical modifications aimed at identifying novel antitrypanosomatidic agents showing higher potency toward PTR1 and increased metabolic stability.

Authors: C. Borsari, R. Luciani, C. Pozzi, I. Poehner, S. Henrich, M. Trande, A. Cordeiro-da-Silva, N. Santarem, C. Baptista, A. Tait, F. Di Pisa, L. Dello Iacono, G. Landi, S. Gul, M. Wolf, M. Kuzikov, B. Ellinger, J. Reinshagen, G. Witt, P. Gribbon, M. Kohler, O. Keminer, B. Behrens, L. Costantino, P. Tejera Nevado, E. Bifeld, J. Eick, J. Clos, J. Torrado, M. D. Jimenez-Anton, M. J. Corral, J. M. Alunda, F. Pellati, R. C. Wade, S. Ferrari, S. Mangani, M. P. Costi

Date Published: 25th Aug 2016

Publication Type: Journal Article

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