Béatrice Silvia Orena

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

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Giorgia Mori

University of Sydney

Maria Rosalia Pasca

University of Pavia

Christian Lherbet

Molécules d'Intérêt Biologique

Lisa Cariani

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Michel Baltas

Laboratoire de Chimie de Coordination

Laurent R. Chiarelli

University of Pavia

Giovanna Riccardi

University of Pavia

Katarı́na Mikus̃ová

Comenius University Bratislava

Jan Madacki

Institut Pasteur

Jana Korduláková

Comenius University Bratislava

Cooperative Institutions

Istituti di Ricovero e Cura a Carattere Scientifico

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

University of Milan

Centre National de la Recherche Scientifique

Ospedale Maggiore

Université Toulouse III - Paul Sabatier

Université de Toulouse

University of Pavia

Vita-Salute San Raffaele University

Molécules d'Intérêt Biologique

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Synthesis and evaluation of β-hydroxytriazoles and related compounds as antitubercular agents

French-Ukrainian Journal of Chemistry (2015)

Christophe Menendez Giorgia Mori Mathilde Maillot Isabelle Fabing Chantal Carayon

A new series of β-hydroxytriazoles were synthesized and evaluated as Mycobacterium tuberculosis inhibitors. Our strategy implied the synthesis of alkyne precursors through a Barbier reaction between benzaldehydes and propargyl bromide followed by click chemistry to afford substituted β-hydroxyl benzyltriazoles. These compounds are also key intermediates either for oxidation reactions leading to α,β-diketotriazoles or for elimination reactions affording styryl triazoles. Evaluation of all new compounds for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv resulted in compounds with MIC up to 7 μM.

Propargyl bromide

Propargyl

Alkyne

10.17721/fujcv3i1p82-96

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Citations (1)

CCDC 1448411: Experimental Crystal Structure Determination

The Cambridge Structural Database (2016)

Damien Veau Serhii Krykun Giorgia Mori Béatrice Silvia Orena Maria Rosalia Pasca

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

10.5517/ccdc.csd.cc1km5y9

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Citations (0)

CCDC 1484634: Experimental Crystal Structure Determination

The Cambridge Structural Database (2016)

Tetiana Matviiuk Jan Madacki Giorgia Mori Béatrice Silvia Orena Christophe Menendez

10.5517/ccdc.csd.cc1ltwfq

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Citations (0)

In search for the active metabolites and the cellular target of the antitubercular prodrug TP053

Laurent R. Chiarelli Béatrice Silvia Orena Giorgia Mori Makarov Fabio Gosetti

Source

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SARS-CoV-2 antibodies among people with cystic fibrosis prior to the vaccination campaign: A seroprevalence study in two specialized centres in Northern Italy

Journal of Cystic Fibrosis (2021)

Gianfranco Alicandro Valeria Daccò Lisa Cariani Martina Contarini Letizia Corinna Morlacchi

Seroprevalence

10.1016/j.jcf.2021.12.011

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Citations (5)

Synthesis, oxidation potential and anti-mycobacterial activity of isoniazid and analogues: insights into the molecular isoniazid activation mechanism

ChemistrySelect (2016)

Julie Laborde Céline Deraeve Léa Lecoq Alix Sournia‐Saquet Jean‐Luc Stigliani

Tuberculosis (TB) is one of the leading causes of death due to infectious diseases. Among the specific drugs currently employed to treat tuberculosis, isoniazid (INH), a pro-drug, attracts a great interest. However, Mycobacterium tuberculosis (MTB) clinical isolates resistant to INH are significantly increasing thus compromising the efficiency of TB-treatment. Concerning the mechanism of resistance to INH, it is nowadays well established that it mainly results from mutations in the katG genes encoding for INH enzymatic activator. Recently, it was proposed that mutation in katG induces differences in heme or side chain redox potential so that the enzyme loses its ability to oxidize INH to radical species. In this work, we synthesized and selected a series of INH analogues for a study of their oxidation potential and evaluation of their anti-TB efficiency toward MTB wild-type and drug resistant strains. On the contrary to what was postulated, no correlation exists between the easier oxidation of a molecule and its anti-MTB activity toward resistant strains. Based on experimental data and theoretical calculations, we proposed an activation mechanism for INH and analogues based on a one-electron oxidation step of the hydrazyl function at the proximal nitrogen followed by a radical transposition to the distal nitrogen, which then induces a β-homolytic cleavage of the C(=O)-N bond to afford diazene and the isonicotinoyl radical species.

10.1002/slct.201600040

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Citations (23)

CCDC 1448413: Experimental Crystal Structure Determination

The Cambridge Structural Database (2016)

Damien Veau Serhii Krykun Giorgia Mori Béatrice Silvia Orena Maria Rosalia Pasca

10.5517/ccdc.csd.cc1km60d

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Triazolophthalazines: Easily Accessible Compounds with Potent Antitubercular Activity

ChemMedChem (2016)

Damien Veau Serhii Krykun Giorgia Mori Béatrice Silvia Orena Maria Rosalia Pasca

Abstract Tuberculosis (TB) remains one of the major causes of death worldwide, in particular because of the emergence of multidrug‐resistant TB. Herein we explored the potential of an alternative class of molecules as anti‐TB agents. Thus, a series of novel 3‐substituted triazolophthalazines was quickly and easily prepared from commercial hydralazine hydrochloride as starting material and were further evaluated for their antimycobacterial activities and cytotoxicities. Four of the synthesized compounds were found to effectively inhibit the Mycobacterium tuberculosis ( M.tb ) H 37 Rv strain with minimum inhibitory concentration (MIC) values <10 μg mL −1 , whereas no compounds displayed cytotoxicity against HCT116 human cell lines (IC 50 >100 μ m ). More remarkably, the most potent compounds proved to be active to a similar extent against various multidrug‐resistant M.tb strains, thus uncovering a mode of action distinct from that of standard antitubercular agents. Overall, their ease of preparation, combined with their attractive antimycobacterial activities, make such triazolophthalazine‐based derivatives promising leads for further development.

Antimycobacterial

Mode of Action

10.1002/cmdc.201600085

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Citations (14)

Active Surveillance of Patients Colonized with CRE: A Single-Center Study Based on a Combined Molecular/Culture Protocol

Antibiotics (2024)

Béatrice Silvia Orena Maria Francesca Liporace Antonio Teri Daniela Girelli Federica Salari

: Carbapenem-resistant

Center (category theory)

10.3390/antibiotics13111053

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New Insights into the Mechanism of Action of the Thienopyrimidine Antitubercular Prodrug TP053

ACS Infectious Diseases (2019)

Laurent R. Chiarelli Elena G. Salina Giorgia Mori Tatyana Azhikina Olga Riabova

The thienopyrimidine TP053 is an antitubercular prodrug active against both replicating and nonreplicating Mycobacterium tuberculosis (M. tuberculosis) cells, which requires activation by the mycothiol-dependent nitroreductase Mrx2. The investigation of the mechanism of action of TP053 revealed that Mrx2 releases nitric oxide from this drug both in the enzyme assays with purified Mrx2 and in mycobacterial cultures, which can explain its activity against nonreplicating bacilli, similar to pretomanid activated by the nitroreductase Ddn. In addition, we identified a highly reactive metabolite, 2-(4-mercapto-6-(methylamino)-2-phenylpyrimidin-5-yl)ethan-1-ol, which can contribute to the antimycobacterial effects on replicating cells as well as on nonreplicating cells. In summary, we explain the mechanism of action of TP053 on both replicating and nonreplicating M. tuberculosis and report a novel activity for Mrx2, which in addition to Ddn, represents another example of nitroreductase releasing nitric oxide from its substrate. These findings are particularly relevant in the context of drugs targeting nonreplicating M. tuberculosis, which is shown to be killed by increased levels of nitric oxide.

Nitroreductase

Mechanism of Action

Antimycobacterial

10.1021/acsinfecdis.9b00388

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Citations (15)