Identification of a 2,4-diaminopyrimidine scaffold targeting Trypanosoma brucei pteridine reductase 1 from the LIBRA compound library screening campaign

Linciano, Pasquale; Cullia, Gregorio; Borsari, Chiara; Santucci, Matteo; Ferrari, Stefania; Witt, Gesa; Gul, Sheraz; Kuzikov, Maria; Ellinger, Bernhard; Cordeiro-da-Silva, Anabela; Conti, Paola; Bolognesi, María Laura; Roberti, Marinella; Prati, Federica; Bartoccini, Francesca; Retini, Michele; Piersanti, Giovanni; Cavalli, Andrea; Goldoni, Luca; Bertozzi, Sine Mandrup; Bertozzi, Fabio; Brambilla, Enzo; Rizzo, Vincenzo; Piomelli, Daniele; Pinto, Andrea; Bandiera, Tiziano; Costi, Maria Paola

doi:10.1016/j.ejmech.2020.112047

Cited by 9 publications

(7 citation statements)

References 61 publications

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“…The HMI-9 medium was selected due to its high folic acid content (9 μM), resulting in efficient parasite growth and enabling process standardization . The same medium was used in our previous experiments and allowed maintenance of similar relative folate metabolism levels between models studied in high- and low-throughput systems, namely, between Trypanosoma cells and mouse models, and between mouse models and human plasma. , Cultures were then diluted to a cell density of 2 × 10 6 /mL. For the assay, compounds were prepared in 10 mM DMSO and diluted in HMI-9 to a 40 μM solution (0.4% DMSO).…”

Section: Methodsmentioning

confidence: 99%

Multitarget, Selective Compound Design Yields Potent Inhibitors of a Kinetoplastid Pteridine Reductase 1

et al. 2022

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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 EC 50 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.

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Section: Methodsmentioning

confidence: 99%

Multitarget, Selective Compound Design Yields Potent Inhibitors of a Kinetoplastid Pteridine Reductase 1

et al. 2022

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“…Besides importance as antiproliferative agents, diaminopyrimidine adducts are also associated as antimicrobial agents, [69][70][71] consequence, the in vitro antimicrobial activities of the synthesized compounds against four strains of bacteria and two of fungi were determined. The selected biological screening data are summarized in Figure 4 (detailed data are available in Table S2 in Supporting Information).…”

Section: Antimicrobial Activitymentioning

confidence: 99%

Divergent Synthesis, Antiproliferative and Antimicrobial Studies of 1,3‐Aminoalcohol and 3‐Amino‐1,2‐Diol Based Diaminopyrimidines

Raji

Huỳnh

et al. 2022

Chemistry & Biodiversity

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A series of novel diaminopyrimidines containing pinane moieties were synthesized via an efficient methodology starting from pinane‐based aminoalcohols, aminodiols and 2,4‐dichloropyrimidines. Bioassay tests demonstrated that compound 18a displayed much stronger antiproliferative activities against four human cancer cell lines (HeLa, Siha, MDA‐MB‐231, MCF‐7 and A2780) than positive control cisplatin. In particular, compound 22a was found to be selective in inhibiting HeLa cell proliferation with cancer cell growth inhibition values higher than 95 %. Moreover, the in vitro screening of prepared compounds against different bacterial and fungal strains is reported. The results revealed that 12b and 17a, the most promising compounds, displayed selective inhibition for the Gram‐positive bacteria (B. subtilis and S. aureus) with percent inhibition values ranging from 75 to 95 % at 10 μg/mL concentration. Both selective inhibition and the in vitro activity values demonstrated that these compounds have the potential to be developed into clinically important therapeutic choices for the treatment of infections caused by B. subtilis and S. aureus.

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“…Some large compound libraries were collected from different consortia (More Medicines for Tuberculosis (MM4TB) , and New Medicine for Trypanosomatidic Infection (NMTrypI) with the aim of finding a new antitubercular and/or an antiparasitic agent − to overcome the unmet medical needs still represented by tuberculosis and parasite infections. The compounds come from a drug discovery and development studies aimed at optimizing the translation of compounds from the discovery phases to the preclinical and clinical models.…”

Section: Introductionmentioning

confidence: 99%

High-Throughput Phenotypic Screening and Machine Learning Methods Enabled the Selection of Broad-Spectrum Low-Toxicity Antitrypanosomatidic Agents

Linciano,

Quotadamo,

Luciani

et al. 2023

J. Med. Chem.

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Broad-spectrum anti-infective chemotherapy agents with activity against Trypanosomes, Leishmania, and Mycobacterium tuberculosis species were identified from a high-throughput phenotypic screening program of the 456 compounds belonging to the Ty-Box, an in-house industry database. Compound characterization using machine learning approaches enabled the identification and synthesis of 44 compounds with broad-spectrum antiparasitic activity and minimal toxicity against Trypanosoma brucei, Leishmania Infantum, and Trypanosoma cruzi. In vitro studies confirmed the predictive models identified in compound 40 which emerged as a new lead, featured by an innovative N-(5-pyrimidinyl)benzenesulfonamide scaffold and promising low micromolar activity against two parasites and low toxicity. Given the volume and complexity of data generated by the diverse high-throughput screening assays performed on the compounds of the Ty-Box library, the chemoinformatic and machine learning tools enabled the selection of compounds eligible for further evaluation of their biological and toxicological activities and aided in the decision-making process toward the design and optimization of the identified lead.

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Identification of a 2,4-diaminopyrimidine scaffold targeting Trypanosoma brucei pteridine reductase 1 from the LIBRA compound library screening campaign

Cited by 9 publications

References 61 publications

Multitarget, Selective Compound Design Yields Potent Inhibitors of a Kinetoplastid Pteridine Reductase 1

Multitarget, Selective Compound Design Yields Potent Inhibitors of a Kinetoplastid Pteridine Reductase 1

Divergent Synthesis, Antiproliferative and Antimicrobial Studies of 1,3‐Aminoalcohol and 3‐Amino‐1,2‐Diol Based Diaminopyrimidines

High-Throughput Phenotypic Screening and Machine Learning Methods Enabled the Selection of Broad-Spectrum Low-Toxicity Antitrypanosomatidic Agents

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