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Instruments / Technical Area	Publication Details	Published
I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Identification of innovative folate inhibitors leveraging the amino dihydrotriazine motif from cycloguanil for their potential as anti-Trypanosoma brucei agents 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 Acs Infectious Diseases 27 DOI: 10.1021/acsinfecdis.4c00113 Diamond Proposal Number(s): [29907] Show Abstract ▼ Abstract: Folate enzymes, namely, dihydrofolate reductase (DHFR) and pteridine reductase (PTR1) are acknowledged targets for the development of antiparasitic agents against Trypanosomiasis and Leishmaniasis. Based on the amino dihydrotriazine motif of the drug Cycloguanil (Cyc), a known inhibitor of both folate enzymes, we have identified two novel series of inhibitors, the 2-amino triazino benzimidazoles (1) and 2-guanidino benzimidazoles (2), as their open ring analogues. Enzymatic screening was carried out against PTR1, DHFR, and thymidylate synthase (TS). The crystal structures of TbDHFR and TbPTR1 in complex with selected compounds experienced in both cases a substrate-like binding mode and allowed the rationalization of the main chemical features supporting the inhibitor ability to target folate enzymes. Biological evaluation of both series was performed against T. brucei and L. infantum and the toxicity against THP-1 human macrophages. Notably, the 5,6-dimethyl-2-guanidinobenzimidazole 2g resulted to be the most potent (Ki = 9 nM) and highly selective TbDHFR inhibitor, 6000-fold over TbPTR1 and 394-fold over hDHFR. The 5,6-dimethyl tricyclic analogue 1g, despite showing a lower potency and selectivity profile than 2g, shared a comparable antiparasitic activity against T. brucei in the low micromolar domain. The dichloro-substituted 2-guanidino benzimidazoles 2c and 2d revealed their potent and broad-spectrum antitrypanosomatid activity affecting the growth of T. brucei and L. infantum parasites. Therefore, both chemotypes could represent promising templates that could be valorized for further drug development.	Jul 2024
I03-Macromolecular Crystallography	The discovery of aryl-2-nitroethyl triamino pyrimidines as anti-Trypanosoma brucei agents 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 European Journal Of Medicinal Chemistry 10 DOI: 10.1016/j.ejmech.2023.115946 Diamond Proposal Number(s): [21741] Show Abstract ▼ Abstract: Pteridine reductase 1 (PTR1) is a catalytic protein belonging to the folate metabolic pathway in Trypanosmatidic parasites. PTR1 is a known target for the medicinal chemistry development of antiparasitic agents against Trypanosomiasis and Leishmaniasis. In previous studies, new nitro derivatives were elaborated as PTR1 inhibitors. The compounds showing a diammino-pyrimidine core structure were previously developed but they showed limited efficacy. Therefore, a new class phenyl-, heteroaryl- and benzyloxy-nitro derivatives of the 2-nitroethyl-2,4,6-triaminopyrimidine scaffold were designed and tested. The compounds were assayed for their ability to inhibit T. brucei and L. major PTR1 enzymes and for their antiparasitic activity towards T. brucei and L. infantum parasites. To understand the structure-activity relationships of the compounds against TbPTR1, the x-ray crystallographic structure of the 2,4,6-triaminopyrimidine (TAP) was obtained and molecular modelling studies were performed. As a next step, only the most effective T. brucei inhibitors were then tested against the amastigote cellular stage of T. cruzi, searching for a broad-spectrum antiprotozoal agent. An early ADME-Tox profile evaluation was performed. The early toxicity profile of this class of compounds was investigated by measuring their inhibition of hERG and five cytochrome P450 isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4), cytotoxicity towards A549 cells and mitochondrial toxicity. Pharmacokinetic studies (SNAP-PK) were performed on selected compounds using hydroxypropyl-β-cyclodextrins (50 % w/v) to preliminarily study their plasma concentration when administered per os at a dose of 20 mg/kg. Finally, compound 1p, selected for the best pharmacodynamic and pharmacokinetic properties, showed promising activity in a mouse model of T. brucei infection. Compound 1p can be considered a good candidate for further bioavailability and efficacy studies.	Nov 2023
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	Multitarget, selective compound design yields potent inhibitors of a kinetoplastid pteridine reductase 1 Ina Pöhner , Antonio Quotadamo , Joanna Panecka-Hofman , Rosaria Luciani , Matteo Santucci , Pasquale Linciano , Giacomo Landi , Flavio Di Pisa , Lucia Dello Iacono , Cecilia Pozzi , Stefano Mangani , Sheraz Gul , Gesa Witt , Bernhard Ellinger , Maria Kuzikov , Nuno Santarem , Anabela Cordeiro-Da-Silva , Maria P. Costi , Alberto Venturelli , Rebecca C. Wade Journal Of Medicinal Chemistry 51 DOI: 10.1021/acs.jmedchem.2c00232 Open Access Show Abstract ▼ Abstract: The optimization of compounds with multiple targets is a difficult multidimensional problem in the drug discovery cycle. Here, we present a systematic, multidisciplinary approach to the development of selective antiparasitic compounds. Computational fragment-based design of novel pteridine derivatives along with iterations of crystallographic structure determination allowed for the derivation of a structure–activity relationship for multitarget inhibition. The approach yielded compounds showing apparent picomolar inhibition of T. brucei pteridine reductase 1 (PTR1), nanomolar inhibition of L. major PTR1, and selective submicromolar inhibition of parasite dihydrofolate reductase (DHFR) versus human DHFR. Moreover, by combining design for polypharmacology with a property-based on-parasite optimization, we found three compounds that exhibited micromolar EC50 values against T. brucei brucei while retaining their target inhibition. Our results provide a basis for the further development of pteridine-based compounds, and we expect our multitarget approach to be generally applicable to the design and optimization of anti-infective agents.	Jun 2022
I03-Macromolecular Crystallography	Evidence of pyrimethamine and cycloguanil analogues as dual inhibitors of Trypanosoma brucei pteridine reductase and dihydrofolate reductase Giusy Tassone , Giacomo Landi , Pasquale Linciano , Valeria Francesconi , Michele Tonelli , Lorenzo Tagliazucchi , Maria Paola Costi , Stefano Mangani , Cecilia Pozzi Pharmaceuticals 14 DOI: 10.3390/ph14070636 Diamond Proposal Number(s): [11690] Open Access Show Abstract ▼ Abstract: Trypanosoma and Leishmania parasites are the etiological agents of various threatening neglected tropical diseases (NTDs), including human African trypanosomiasis (HAT), Chagas disease, and various types of leishmaniasis. Recently, meaningful progresses in the treatment of HAT, due to Trypanosoma brucei (Tb), have been achieved by the introduction of fexinidazole and the combination therapy eflornithine–nifurtimox. Nevertheless, due to drug resistance issues and the exitance of animal reservoirs, the development of new NTD treatments is still required. For this purpose, we explored the combined targeting of two key folate enzymes, dihydrofolate reductase (DHFR) and pteridine reductase 1 (PTR1). We formerly showed that the TbDHFR inhibitor cycloguanil (CYC) also targets TbPTR1, although with reduced affinity. Here, we explored a small library of CYC analogues to understand how their substitution pattern affects the inhibition of both TbPTR1 and TbDHFR. Some novel structural features responsible for an improved, but preferential, ability of CYC analogues to target TbPTR1 were disclosed. Furthermore, we showed that the known drug pyrimethamine (PYR) effectively targets both enzymes, also unveiling its binding mode to TbPTR1. The structural comparison between PYR and CYC binding modes to TbPTR1 and TbDHFR provided key insights for the future design of dual inhibitors for HAT therapy.	Jun 2021
I02-Macromolecular Crystallography	High-resolution crystal structure of Trypanosoma brucei pteridine reductase 1 in complex with an innovative tricyclic-based inhibitor Giacomo Landi , Pasquale Linciano , Giusy Tassone , Maria Paola Costi , Stefano Mangani , Cecilia Pozzi Acta Crystallographica Section D Structural Biology 76, 558 - 564 DOI: 10.1107/S2059798320004891 Diamond Proposal Number(s): [11690] Show Abstract ▼ Abstract: The protozoan parasite Trypanosoma brucei is the etiological agent of human African trypanosomiasis (HAT). HAT, together with other neglected tropical diseases, causes serious health and economic issues, especially in tropical and subtropical areas. The classical antifolates targeting dihydrofolate reductase (DHFR) are ineffective towards trypanosomatid parasites owing to a metabolic bypass by the expression of pteridine reductase 1 (PTR1). The combined inhibition of PTR1 and DHFR activities in Trypanosoma parasites represents a promising strategy for the development of new effective treatments for HAT. To date, only monocyclic and bicyclic aromatic systems have been proposed as inhibitors of T. brucei PTR1 (TbPTR1); nevertheless, the size of the catalytic cavity allows the accommodation of expanded molecular cores. Here, an innovative tricyclic-based compound has been explored as a TbPTR1-targeting molecule and its potential application for the development of a new class of PTR1 inhibitors has been evaluated. 2,4-Diaminopyrimido[4,5-b]indol-6-ol (1) was designed and synthesized, and was found to be effective in blocking TbPTR1 activity, with a Ki in the low-micromolar range. The binding mode of 1 was clarified through the structural characterization of its ternary complex with TbPTR1 and the cofactor NADP(H), which was determined to 1.30 Å resolution. The compound adopts a substrate-like orientation inside the cavity that maximizes the binding contributions of hydrophobic and hydrogen-bond interactions. The binding mode of 1 was compared with those of previously reported bicyclic inhibitors, providing new insights for the design of innovative tricyclic-based molecules targeting TbPTR1.	Jun 2020
I02-Macromolecular Crystallography	Structural insights into the development of cycloguanil derivatives as Trypanosoma brucei pteridine reductase 1 inhibitors Giacomo Landi , Pasquale Linciano , Chiara Borsari , Claudia P. Bertolacini , Carolina Borsoi Moraes , Anabela Cordeiro-Da-Silva , Sheraz Gul , Gesa Witt , Maria Kuzikov , Maria Paola Costi , Cecilia Pozzi , Stefano Mangani Acs Infectious Diseases DOI: 10.1021/acsinfecdis.8b00358 Diamond Proposal Number(s): [11690] Show Abstract ▼ Abstract: Cycloguanil is a known dihydrofolate reductase (DHFR) inhibitor, but there is no evidence of its activity on pteridine reductase (PTR), the main metabolic bypass to DHFR inhibition in trypanosomatid parasites. Here, we provide experimental evidence of cycloguanil as an inhibitor of Trypanosoma brucei PTR1 (TbPTR1). A small library of cycloguanil derivatives was develop, resulting in 1 and 2a having IC50 of 692 and 186 nM, respectively, towards TbPTR1. Structural analysis revealed that the increased potency of 1 and 2a is due to the combined contributions of hydrophobic interactions, H-bonds and halogen bonds. Moreover, in vitro cell growth inhibition tests indicated that 2a is also effective on T. brucei. The simultaneous inhibition of DHFR and PTR1 activity in T. brucei is a new promising strategy for the treatment of human African Trypanosomiasis. On this purpose, 1,6-dihydrotriazines represent new molecular tools to develop potent dual PTR and DHFR inhibitors.	Apr 2019
I04-Macromolecular Crystallography	Exploiting the 2-amino-1,3,4-thiadiazole scaffold to inhibit Trypanosoma brucei pteridine reductase in support of early-stage drug discovery Pasquale Linciano , Alice Dawson , Ina Pöhner , David M. Costa , Monica S. Sá , Anabela Cordeiro-Da-Silva , Rosaria Luciani , Sheraz Gul , Gesa Witt , Bernhard Ellinger , Maria Kuzikov , Philip Gribbon , Jeanette Reinshagen , Markus Wolf , Birte Behrens , Véronique Hannaert , Paul A. M. Michels , Erika Nerini , Cecilia Pozzi , Flavio Di Pisa , Giacomo Landi , Nuno Santarem , Stefania Ferrari , Puneet Saxena , Sandra Lazzari , Giuseppe Cannazza , Lucio H. Freitas-Junior , Carolina B. Moraes , Bruno S. Pascoalino , Laura M. Alcântara , Claudia P. Bertolacini , Vanessa Fontana , Ulrike Wittig , Wolfgang Müller , Rebecca C. Wade , William N. Hunter , Stefano Mangani , Luca Costantino , Maria P. Costi Acs Omega 2, 5666 - 5683 DOI: 10.1021/acsomega.7b00473 Diamond Proposal Number(s): [8574] Open Access Show Abstract ▼ Abstract: 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 μM, 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.	Sep 2017
I04-Macromolecular Crystallography	Chroman-4-one derivatives targeting pteridine reductase 1 and showing anti-parasitic activity Flavio Di Pisa , Giacomo Landi , Lucia Dello Iacono , Cecilia Pozzi , Chiara Borsari , Stefania Ferrari , Matteo Santucci , Nuno Santarem , Anabela Cordeiro-Da-Silva , Carolina Moraes , Laura Alcantara , Vanessa Fontana , Lucio Freitas-Junior , Sheraz Gul , Maria Kuzikov , Birte Behrens , Ina Pöhner , Rebecca Wade , Maria Costi , Stefano Mangani Molecules 22 DOI: 10.3390/molecules22030426 Diamond Proposal Number(s): [8574] Open Access Show Abstract ▼ Abstract: 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.	Mar 2017
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Profiling of flavonol derivatives for the development of antitrypanosomatidic drugs Chiara Borsari , Rosaria Luciani , Cecilia Pozzi , Ina Poehner , Stefan Henrich , Matteo Trande , Anabela Cordeiro-Da-Silva , Nuno Santarem , Catarina Baptista , Annalisa Tait , Flavio Di Pisa , Lucia Dello Iacono , Giacomo Landi , Sheraz Gul , Markus Wolf , Maria Kuzikov , Bernhard Ellinger , Jeanette Reinshagen , Gesa Witt , Philip Gribbon , Manfred Kohler , Oliver Keminer , Birte Behrens , Luca Costantino , Paloma Tejera Nevado , Eugenia Bifeld , Julia Eick , Joachim Clos , Juan Torrado , María D. Jiménez-Antón , María J. Corral , José M Alunda , Federica Pellati , Rebecca C. Wade , Stefania Ferrari , Stefano Mangani , Maria Paola Costi Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.6b00698 Diamond Proposal Number(s): [11690] Open Access Show Abstract ▼ Abstract: 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 μM. 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 μM, 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.	Aug 2016

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